Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 7-Day Trial for You or Your Team.

Learn More →

The ErbB signaling network: receptor heterodimerization in development and cancer

The ErbB signaling network: receptor heterodimerization in development and cancer The EMBO Journal Vol. 19 No.13 pp.3159-3167, 2000 NEW EMBO MEMBERS' REVIEW The ErbB signaling network: receptor heterodimerization in development and cancer differentiation. Moreover, deregulated expression of ErbB Monilola A.Olayioye, Richard M.Neve 1, receptors, in particular ErbB 1 and ErbB2, has been Heidi A.Lane and Nancy E.Hynes implicated in the development and malignancy of Friedrich Miescher Institute, PO Box 2543, CH-4002 Basel, numerous types of human cancers. The ErbB family has Switzerland evolved from a single ligand-receptor combination in Present address: UCSF, 505 Parnassus/Box 1270, San Francisco, Caenorhabditis elegans (Aroian et al., 1990), through CA 94143-1270, USA Drosophila with one receptor and four ligands Corresponding author (Wasserman and Freeman, 1997), to vertebrates, where e-mail: [email protected] four ErbB receptors bind multiple EGF-related ligands. Consequently, numerous ErbB homo- and heterodimer combinations are possible in vertebrates, suggesting that Keywords: breast cancer/EGF-related growth factors/ the ErbB receptor family has evolved to provide a high mammary gland development/receptor tyrosine kinases/ degree of signaling diversity; an event that may have been signal transduction cascades necessary for the development of metazoans. With this in mind, we have attempted, in this short review, not only to discuss generally individual ErbB receptors and their Introduction signaling potential but also to provide examples of specific ErbB heterodimers in signaling and development. Our Cells are continuously exposed to diverse stimuli ranging particular emphasis will be on their role in mammary from soluble endocrine and paracrine factors, to signaling gland biology, an organ in which the ErbB family and its molecules on neighboring cells. It is of great importance ligands are critically involved in development, differenti­ that these extracellular signals are correctly interpreted by ation and cancer. the cell, in order to achieve an appropriate developmental or proliferative response. Receptors of the tyrosine kinase family play pivotal roles in this process. By binding to The ErbB receptors in development specific peptide ligands they are able to integrate these external stimuli with internal signal transduction path­ The importance of ErbB receptors in development is ways, contributing in this fashion to the ability of the cell proven from the analysis of genetically modified mice. to respond correctly to its environment. In this review, we Indeed, null mutations in individual ErbB loci are lethal. will concentrate on the role of ErbB receptors as normal More specifically, depending upon the genetic background signal transducers and their contribution to the process of of the host, loss of ErbB 1 leads to embryonic or perinatal malignant transformation during tumor development. lethality with mice showing abnormalities in multiple ErbB proteins belong to subclass I of the superfamily of organs including the brain, skin, lung and gastrointestinal receptor tyrosine kinases (RTKs). There are four members tract (Miettinen et al., 1995; Sibilia and Wagner, 1995; of the ErbB family: epidermal growth factor (EGF) Threadgill et al., 1995; Sibilia et al., 1998). ErbB2 null receptor (also termed ErbB 1/HERl), ErbB2/Neu/HER2, mice die at midgestation (El0.5) due to trabeculae ErbB3/HER3 and ErbB4/HER4. We will refer to them, malformation in the heart (Lee et al., 1995), a phenotype henceforth, as the ErbB receptors. All family members that is shared by ErbB4 knockout mice (Gassmann et al., have in common an extracellular ligand-binding domain, a 1995). In addition, through genetic rescue of heart development via myocardial expression of an ErbB2 single membrane-spanning region and a cytoplasmic protein tyrosine kinase domain. A family of ligands, the transgene, a further role for ErbB2 in peripheral nervous EGF-related peptide growth factors, bind the extracellular system development has been demonstrated (Morris et al., domain of ErbB receptors leading to the formation of both 1999). In the case of ErbB3, most knockout mice die by homo- and heterodimers. Dimerization consequently E13.5, displaying normal heart trabeculation but defective stimulates the intrinsic tyrosine kinase activity of the valve formation. Additionally, these animals show a receptors and triggers autophosphorylation of specific generalized neural crest defect and lack Schwann cell tyrosine residues within the cytoplasmic domain. These precursors (Riethmacher et al., 1995; Erickson et al., phosphorylated residues serve as docking sites for signal­ 1997). From these data it is clear that ErbB receptors play ing molecules involved in the regulation of intracellular critical roles in modulating specific aspects of vertebrate signaling cascades. Ultimately, downstream effects on embryogenesis/development. gene expression determine the biological response to It is apparent, however, that ErbB receptors also play receptor activation. essential roles in the adult organism. The mammary gland ErbB receptors are expressed in a variety of tissues of is an organ that undergoes most of its proliferation and epithelial, mesenchymal and neuronal origin, where they differentiation postnatally. At birth, the gland has a play fundamental roles in development, proliferation and rudimentary system of ducts, which undergoes extensive © European Molecular Biology Organization 3159 M.A.Olayioye et al. development at puberty under the influence of steroid and BTC peptide hormones. During pregnancy, lobuloalveolar pro­ EGF NRG-I NRG -3 HB-EGF liferation occurs and, at parturition, the mammary fat pad LIGAND AR NRG-2 RG-4 EPR is completely filled with milk-producing lobuloalveolar TGFa units (Hennighausen and Robinson, 1998). In the mammary gland, all four ErbB receptors are expressed in cell type- and developmental stage-specific patterns (Schroeder and Lee, 1998; Darcy et al., 2000). Embryonic ... or early lethality has prevented direct analyses of mammary glands from ErbB receptor negative mice. However, other approaches have revealed the importance of functional ErbB receptors in this organ. In the case of rbB ErbBl, which is expressed at all stages of mammary gland RECEPTOR development, mice (wa-2) harboring a mutation in the ErbB 1 kinase domain exhibit sparse development of the mammary gland, indicative of defective ductal growth (Fowler et al., 1995). A major role for ErbBl in Fi . 1. Binding specificities of the EGF-related peptide growth factors. ductal growth was further confirmed by expression of There are four categories of ligands that bind ErbB family receptors. dominant-negative (DN) ErbB 1 in the mammary gland EGF, AR and TGFa bind ErbBl; BTC, HB-EGF and EPR bind ErbBI (Xie et al., 1997), as well as by reconstitution experiments and ErbB4; NRG-I and NRG-2 bind ErbB3 and ErbB4; and NRG-3 1 and NRG-4 bind ErbB4. See the text for more details. with ErbB1- - neonatal mammary glands (Wiesen et al., 1999). In contrast, despite the fact that ErbB2 is also expressed at all developmental stages, transgenics express­ and glial growth factor, reflecting the different biological ing DN ErbB2 in the mammary gland display normal ductal growth. These mice do appear, however, to have systems in which this ligand was first described (see Peles defective lobuloalveoli and reduced milk protein secretion and Yarden, 1993). Despite the large number of ligands so (Jones and Stem, 1999). As with ErbB2, transgenics far identified for ErbBl, 3 and 4, as well as intensive expressing DN ErbB4 in the mammary gland exhibit efforts, no direct ligand for ErbB2 has yet been discovered. normal ductal growth but impaired lactation (F. E.Jones However, increasing evidence suggests that the primary et al., 1999). Consequently, a role in lactation has also function of ErbB2 is as a coreceptor. In fact, ErbB2 is the been suggested for ErbB4, correlating with its elevated preferred heterodimerization partner for all other ErbB expression during pregnancy and lactation. ErbB3 is also family members (Figure 2) (Tzahar et al., 1996; Graus­ expressed throughout development; however, a detailed Porta et al., 1997) and plays a role in the potentiation of analysis of its function has not been described. In ErbB receptor signaling (Beerli et al., 1995; Graus-Porta summary, these data clearly suggest that the major et al., 1995). function of ErbB 1 in mammary gland development is in promoting ductal growth, while ErbB2 and ErbB4 appear Controlled expression determines ErbB ligand to have key roles in lobuloalveolar differentiation and availability lactation. Signaling diversity emanating from the ErbB family is generated by the repertoire of ErbB ligands and the combinatorial properties of induced receptor dimers. With ErbB ligands the exception of EGF, which is found in many body fluids, ErbB receptors are activated by a number of ligands, ErbB ligands generally act over short distances as referred to as EGF-related peptide growth factors autocrine or paracrine growth factors. The availability of (reviewed in Peles and Yarden, 1993; Riese and Stem, a specific ligand is, therefore, one way to control its 1998). These are produced as transmembrane precursors, signaling ability. In this respect, ErbB ligands demonstrate and are processed and released by proteolysis (Massague distinct expression patterns that are organ- and develop­ and Pandiella, 1993). There are numerous ErbB-specific mental stage-specific. Some ligands, such as NRG-1, are ligands, summarized in Figure 1, each with an EGF-like widely expressed (Meyer and Birchmeier, 1995) while domain that is sufficient to confer binding specificity. others show more restricted expression profiles. For These include EGF, amphiregulin (AR) and transforming example, the pancreas has high amounts of NRG-4 growth factor-a (TGFa), which bind specifically to (Harari et al., 1999), NRG-3 expression is restricted to ErbBl, and betacellulin (BTC), heparin-binding EGF developing and adult nervous system (Zhang et al., 1997) (HB-EGF) and epiregulin (E PR), which exhibit dual and EPR is high in macrophages and placenta (Toyoda specificity in that they bind both ErbB 1 and ErbB4. The et al., 1997). An extreme example for highly controlled neuregulins (NRG) comprise the third ligand family. expression, both with respect to tissue and time, is NRG-1 and NRG-2 (Riese et al., 1995; Busfield et al., HB- EGF, which is induced in the uterine luminal 1997; Carraway et al., 1997; Chang et al., 1997) both bind epithelium solely at the site of blastocyst apposition 6- ErbB3 and ErbB4, whereas the more recent additions to 7 h prior to uterine implantation (Paria et al., 1999). the NRG family, NRG-3 (Zhang et al., 1997) and NRG-4 In the case of the mammary gland, ErbB 1 ligands and (Harari et al., 1999), bind ErbB4 but not ErbB3. It should NRG- I are co-expressed at various developmental stages be stated that NRG- I is also known as neu differentiation (Yang et al., 1995; Schroeder and Lee, 1998). In order to factor, heregulin, acetylcholine receptor-inducing activity investigate their functional role during mammary gland 3160 The ErbB signaling network BTC et al., 1998). This implies that low-affinity ligands may be IEGF u RG-1 RG-1 even more potent signal inducers than their high-affinity counterparts, a possibility that should be examined more thoroughly. A third property of ErbB ligand binding is the pH stability of the ligand-receptor interaction, which influences receptor trafficking. For example, ligands such as EGF, whose receptor interaction is relatively pH resistant, target ErbB 1 to lysosomes, whereas TGFa and NRG-1 readily dissociate from their respective receptors at endosomal pH, resulting in receptor recycling (French Fig. 2. ErbB2 is the preferred dimerization partner for the other ErbB et al., 1995; Waterman et al., 1998). Subsequent rerouting receptors. Ligand binding to ErbBI (EGF), ErbB3 (NRG-I) or ErbB4 (NRG-I, BTC) induces the formation of receptor homodimers and of the receptor to the plasma membrane may, therefore, ErbB2-containing heterodimers. ErbB3 homodimers do not signal play a major role in signal potentiation. These ligand­ (indicated by the X), since the receptor has impaired kinase activity. specific characteristics provide an extra level of control, Only some of the possible ligand-receptor-induced combinations are contributing to the diversity and fine-tuning of cellular indicated in the figure for the sake of simplicity. responses to ErbB receptor activation. Such elaborate mechanisms reflect the importance of this receptor family in proliferation and differentiation. development, mice with individual targeted disruption of EGF, AR and TGFa, as well as triple null mice, have been generated (Luetteke et al., 1999). Analysis of these mice Major signaling pathways activated by ErbB has indicated that, while there is functional redundancy in receptors the roles of these ErbB ligands, some ligands make Overlapping and specific ErbB substrates specific contributions to mammary gland development. Ligand binding drives receptor dimerization, leading to For example, of the three ligands, AR expression is highest activation of the intrinsic tyrosine kinase and autophos­ in the developing ducts and only AR deficiency is phorylation of specific, C-terminal tyrosine residues associated with impaired ductal growth. This suggests (reviewed in Heldin, 1995; Weiss and Schlessinger, that AR plays an essential, non-redundant role in this 1998) that provide docking sites for proteins containing process. In contrast, however, lobuloalveolar development Src homology 2 (SH2) or phosphotyrosine binding (PTB) of lactating glands in AR null mice appears normal, domains (reviewed in Shoelson, 1997; Sudol, 1998). These whereas in triple null mice lactogenesis is abrogated include adaptor proteins such as She, Crk, Grb2, Grb7 and (Luetteke et al., 1999). Taken together, these data imply Gabl; kinases such as Src, Chk and phosphatidylinositol that functional differentiation of the mammary gland 3-kinase (PI3K; via the p85 regulatory subunit); and the requires the cooperation of multiple ErbB ligands. protein tyrosine phosphatases SHPl and SHP2. Each ErbB receptor displays a distinct pattern of C-terminal autophos­ Distinct biochemical properties of the ligands give phorylation sites. Examination of the binding preferences rise to signaling diversity of a variety of different SH2 and PTB domains, using Signaling diversity depends not only on the presence of a BioCore or phosphopeptide competition assays, combined specific ErbB receptor and its ligand, but also on the with studies utilizing receptor autophosphorylation site biochemical characteristics of the individual ErbB ligands. mutants and co-immunoprecipitation approaches, has First, ErbB ligands are bivalent, a property that determines enabled the identification of effector proteins that couple which receptor dimers are formed, thereby influencing the to specific ErbB phosphotyrosine residues (Figure 3). signaling pathways activated (Beerli and Hynes, 1996; From these analyses, it has become evident that there is a Riese et al., 1996). This biochemical feature bestows upon great deal of overlap in the signaling pathways activated the ligands, therefore, the ability to diversify signaling by the four ErbB receptors. Indeed, all ErbB family possibilities. Ligand bivalency has been implied from members, including the Drosophila and C.elegans homo­ biophysical (Lemmon et al., 1997), structure-function logs DER and Let23, couple via She and/or Grb2 to (Groenen et al., 1994) and immunological approaches the mitogen-activated protein (MAP) kinase pathway. (Katsuura and Tanaka, 1989). In the case ofNRG-1, using However, there are also examples of preferential modu­ a recombinant chimeric ligand (Barbacci et al., 1995; lation of specific pathways. For example, due to the Tzahar et al., 1997), it has been demonstrated that major presence of multiple binding sites for p85, ErbB3 is the determinants required for high-affinity binding to the most efficient activator of PI3K (Prigent and Gullick, primary ErbB receptor (ErbB3 or ErbB4) are contained 1994). In a similar vein, Eps15 and Cbl are examples of within the N-terminus, whilst the C-terminus recruits the ErbBl-specific substrates (Fazioli et al., 1993; Levkowitz second ErbB partner. The second partner is preferentially et al., 1996), both of which are involved in receptor ErbB2 (Tzahar et al., 1997), which has also been shown to downregulation. Eps15 binds the clathrin adaptor protein increase the affinity of ligand binding to all ErbB receptor complex AP-2 and participates in coated-pit-mediated heterodimers (J.Y.Jones et al., 1999). A second biochem­ internalization (Torrisi et al., 1999). Interestingly, in ical property of ErbB peptides is their differential binding contrast to other ErbB receptors, activated ErbB 1 is affinities, a characteristic that influences signal strength rapidly internalized via clathrin-mediated endocytosis and duration. In this respect, virally encoded, low-affinity (Baulida et al., 1996), a phenomenon perhaps related to ErbB-binding peptides have been demonstrated to hinder its specificity for Eps15. Moreover, Drosophila and normal receptor downregulation and degradation (Tzahar C.elegans Cbl orthologs are known to regulate RTK 3161 M.A.Ola io e et a/. y y ErbB4 ErbBJ ErbB2 ErbB3 ErbB-induced biological responses In order to assess the role of autophosphorylation sites in a specific response, individual tyrosine residues have been restored to ErbB mutants lacking the major autophos­ I!* phorylation sites. These are referred to as 'add-back' ll 7R mutants. This approach has mainly been used to examine llMO signaling from the Neu receptor, the rat ErbB2 equivalent. NeuT is the oncogenic variant of Neu, originally dis­ 1203/0S covered in rat neuroectodermal tumors. This mutant receptor possesses a single mutation that alters the 1 241 transmembrane domain (Bargmann et al., 1986), leading she 1 243 to constitutive receptor dimerization (Weiner et al., 1989). Mutation of NeuT autophosphorylation sites 1 2 5 7 she causes a dramatic reduction in its transforming ability. she she 1270 Surprisingly, four of the tyrosine residues when 'added she ehk back' individually fully restore the oncogenicity of NeuT. This demonstrates that, with respect to transformation potential, these tyrosines are functionally redundant Fig. 3. Specific phosphotyrosine residues and binding of signaling (Dankort et al., 1997). In contrast, analyses of transgenic molecules to the ErbB RTKs. ErbBl: tyrosine residues that have been identified as autophosphorylation sites (Downward et al., 1984; Hsuan nematodes expressing Let23 add-back mutants revealed et al., 1989; Margolis et al., 1989; Walton et al., 1990) (in yellow) and that individual tyrosines confer distinct biological func­ sites for the Src kinase (Stover et al., 1995) (in black), including Y845 tions. Viability and vulval differentiation were induced by in the T loop of the kinase domain (shown by an asterisk) (Sato et al., each of three tyrosine residues in a Ras-dependent manner, 1995; Biscardi et al., 1999a), are indicated. Some of the proteins that whereas a single tyrosine was sufficient to confer fertility have been shown to interact with specific tyrosine residues of ErbB 1 are indicated: She binds via its PTB domain to Y1173 and Y1148, and (Lesa and Sternberg, 1997). Comparison of the results via its SH2 domain to Y1173 (Batzer et al., 1994; Okabayashi et al., from these two analyses suggests that once multiple 1994; Sakaguchi et al., 1998); PLCy binds to Yl 173 (Chattopadhyay biological responses can be surveyed, more roles for et al., 1999) and Y992 (Rotin et al., 1992); the major and minor individual tyrosine residues and the pathways to which binding sites for Grb2 are, respectively, Y1068 and Y1086 (Batzer et al., 1994; Okutani et al., 1994); Cbl binds Y1045 (Levkowitz et al., they couple will be uncovered. 1999); SHP1 binds to Y1173 (Keilhack et al., 1998). ErbB2: tyrosine residues that have been identified as autophosphorylation sites are indicated (Hazan et al., 1990; Segatto et al., 1990). Proteins that have The power of ErbB receptor been shown to interact with specific tyrosine residues are indicated: heterodimerization She binds via its PTB domain to Yl 196 and Y1248, and via its SH2 domain to Y1248 and Y1221/2 (Ricci et al., 1995); the latter site has ErbB heterodimers provide signal diversification also been identified in Neu (Dankort et al., 1997); Grb2 binds Yl 139 The ability of ErbB ligands to induce not only receptor (Ricci et al., 1995) and the equivalent residue in Neu (Dankort et al., homodimers but also heterodimers expands ErbB signal­ 1997); Chk binds Y1248 (Zrihan-Licht et al., 1998). ErbB3: ing potential. Heterodimerization follows a strict hier­ phosphopeptide analyses of in viva labeled ErbB3 have not been published. The p85 subunit of PI3K and the She binding sites have archical principle with ErbB2 representing the preferred been mapped by phosphopeptide competition (Prigent and Gullick, dimerization partner of all other ErbB receptors (Figure 2) 1994). Peptides encompassing Y1035 and Y1270 compete strongly, (Tzahar et al., 1996; Graus-Porta et al., 1997). This peptides encompassing Y1178, Y1203/05, Y1241 and Y1257 compete phenomenon can be explained, as discussed above, by the less strongly for p85 binding; a peptide encompassing Y1309 competes for She binding. The major and minor sites for Grb7 binding are, binding preferences of the bivalent ligands. Thus, the ErbB respectively, Y1180 and Y1243 (Fiddes et al., 1998). ErbB4: dimers formed are dictated by the nature of the ligand and phosphopeptide analyses of in viva labeled ErbB4 have not been the cell's complement of ErbB receptors. ErbB2-contain­ published. Phosphopeptide competition analyses have shown that She ing heterodimers display increased ligand affinity due to a binds Y1242 and Yl 188 (Cohen et al., 1996b); the p85 subunit of decelerated off-rate (Karunagaran et al., 1996) that can be PI3K binds Y1056 (Elenius et al., 1999). (Only the cytoplasmic domains of the four ErbB RTKS are shown; for graphic purposes, the correlated with prolonged activation of downstream sig­ receptors have not been aligned.) naling pathways (Beerli et al., 1995; Graus-Porta et al., 1995). Furthermore, biological responses such as prolif­ eration (Beerli et al., 1995; Graus-Porta et al., 1995), signaling negatively (Yoon et al., 1995; Meisner et al., morphological differentiation (Beerli et al., 1995) and 1997); however, the mechanism by which this protein acts migration/invasion (Spencer et al., 2000) are enhanced in was only recently resolved. Cbl was identified as a RING cells expressing ErbB2. finger domain-containing E3 ubiquitin protein ligase ErbB heterodimerization is a means not only for signal (Joazeiro et al., 1999; Yokouchi et al., 1999), required amplification but also for signal diversification. The for ErbB 1 ubiquitylation and targeting of the receptor to subsets of SH2-and PTB-binding signaling molecules the lysosomal compartment (Levkowitz et al., 1999). recruited to an activated receptor are defined by the pattern These results help explain the dramatic decrease in ErbB 1 of phosphorylated tyrosine residues in the C-terminus of levels caused by ligand activation, something not observed the receptor (Figure 3). Based on our finding that the Cbl for the other ErbB receptors. Taken together, it is clear that protein coupled only to EGF- but not to NRG-activated ErbB receptors couple to specific downstream, intracel­ ErbB 1 (Graus-Porta et al., 1997), we speculated that signal lular pathways with differing efficiencies, thus affording diversification arises at one level by differential transphos­ greater signaling possibilities. phorylation of a given receptor in distinct ErbB dimers. By 3162 The ErbB signaling network phosphopeptide mapping of activated ErbB 1 and ErbB2 specific neuroendocrine sites. LHRH is essential for sexual from NIH 3T3 cells expressing single and pairwise development and adult reproductive function. In this combinations of ErbB receptors, we were able to prove respect, loss of ErbB2 function has been shown to delay that receptor phosphorylation is indeed modulated by the the onset of puberty, by preventing LHRH secretion, dimerization partner (Olayioye et al., 1998). This provides despite the continued presence of ErbB4 and NRG (Ojeda a biochemical explanation for the observation that EGF­ and Ma, 1999). ErbB receptor heterodimers, therefore, activated ErbBl, but not ErbBl heterodimerized with play significant roles in a number of developmental ErbB4, was able to recruit Grb2 (Olayioye et al., 1998). processes-roles that cannot be performed by homo­ Furthermore, despite similar levels of total phosphotyr­ dimers. This is indicative of the need to control receptor osine, ErbB2 constitutively dimerized due to a mutation in signaling precisely during development, and again reflects the transmembrane domain was considerably more potent the evolutionary diversification of this family of receptors in binding She than ErbB2 transactivated by EGF in metazoans. (Olayioye et al., 1998). Thus, the signal elicited by a receptor heterodimer is not simply the sum of the signaling ErbB receptors as signal integrators properties of the individual dimerization partners, but is In the past years it has become clear that there are also rather due to unique properties acquired by the hetero­ additional layers of complexity to the ErbB receptor dimer. For example, IL-3-dependent Ba/F3 cells engin­ system. For instance, ErbB RTKs integrate signaling eered to co-express ErbBl and ErbB4 demonstrate IL-3-events emanating from other receptor classes, such as independent proliferation in the presence of NDF or EGF. G-protein-coupled receptors and cytokine receptors. However, neither ligand promotes IL-3-independent pro­ Moreover, even in the absence of ErbB kinase activity, liferation of cells that individually express ErbB 1 or phosphorylation of specific residues in the cytoplasmic tail ErbB4 (Riese et al., 1996). Similarly, NRG-induced of the receptor by non-receptor kinases such as Jak and Src ErbB2- ErbB4 heterodimers activate the transcription can provide docking sites for cytoplasmic signaling factor Stat5 while homodimers of either receptor fail to molecules. Thus, in these cases, the receptor is simply do so (Olayioye et al., 1999). used as a scaffold protein, transmitting information to Continuing in this context, it should be noted that ErbB3 downstream signaling pathways. A detailed description of is an impaired kinase due to substitutions in critical these interactions is outside the scope of this article and residues in its kinase domain (Guy et al., 1994). Hence, the reader is referred to recent reviews on the different despite having multiple ligands, ErbB3 only functions as a modes of ErbB receptor activation (Biscardi et al., 1999b; signaling entity when complexed with another ErbB Carpenter, 1999; Hackel et al., 1999; Luttrell et al., 1999). receptor. Therefore, the process of ErbB heterodimeriza­ To date, most work in the area of signal transduction tion enables the integration of a ligand-less ErbB2 and a has concentrated on membrane-proximal events. Con­ kinase-defective ErbB3 into signal transduction processes. sequently, downstream effects on gene expression, result­ In fact, a consensus is emerging that the ErbB2- ErbB3 ing in the modulation of specific biological/developmental heterodimer is the most potent ErbB signaling complex in programs, are still scantily described. New technologies terms of in vitro growth and transformation (Alimandi such as nucleotide arrays and proteomics will help et al., 1995; Pinkas-Kramarski et al., 1996). elucidate the issue by providing more information on how ErbB receptor signaling impinges on the expression Biological effects of ErbB heterodimers of multiple genes and proteins. The ultimate goal will be to Phenotypes of ErbB receptor knock-out mice are the most understand the interplay of ErbB RTKs and their ligands in striking proof of the power of receptor heterodimers. Mice the context of the entire signaling network present in an individually null for ErbB2, ErbB4 or NRG-1 each organ. demonstrate a lack of trabeculae formation in the heart (Gassmann et al., 1995; Lee et al., 1995; Meyer and ErbB receptors in cancer: a special focus Birchmeier, 1995; Kramer et al., 1996), showing that an on ErbB cooperation important signaling moiety in the myocardium is the There is a wealth of clinical data demonstrating the ErbB2- ErbB4 heterodimer stimulated in a paracrine fashion by NRG-1. The essential contribution of this importance of ErbB receptors, in particular ErbB 1 and receptor collaboration to heart development is clearly ErbB2, in the development and malignancy of human observed in ErbB2 null mice, where NRG- I -induced cancer. However, considering the brevity and the theme of ErbB4 dimers cannot replace the function of the ErbB2- this review only examples of ErbB receptor synergy will ErbB4 heterodimer. Ligand-induced ErbB2- ErbB3 be discussed. The interested reader is referred to these heterodimers also play an important role in nervous system reviews (Hynes and Stem, 1994; Salomon et al., 1995; development. Indeed, mice individually mutant for ErbB2, Tang and Lippman, 1998) for more detailed information. ErbB3 or NRG-1 display a failure in neural crest cell Cooperation between ErbB receptors has been observed in migration, leading to impaired formation of the sympa­ oncogenic transformation, both in vitro in cultured cells thetic nervous system (Britsch et al., 1998). A further and in primary human tumors. Following the initial example of in vivo ErbB cooperation is provided by a observation that co-expression of ErbB2 with ErbB 1 in specific function for these receptors in the hypothalamus. NIH 3T3 fibroblasts augmented the effects of EGF on the Here, before the onset of puberty, NRG-mediated acti­ transformed phenotype (Kokai et al., 1989), there vation of ErbB2 and ErbB4 is required for the release of have been numerous studies on the collaboration of prostaglandin E2, which then controls the secretion of ErbB receptors in transformation. For example, ErbB3 luteinizing hormone-releasing hormone (LHRH) from expression increases ErbB2-mediated transformation and 3163 M.A.Ola io e et al. y y tumorigenic growth in NIH 3T3 cells. Also, NRG-1- achieved through the use of single-chain antibody (scFv) induced transformation of fibroblasts by ErbB4 requires technology (Beerli et al., 1994; Neve et al., 2000). These co-expression of either ErbB 1 or ErbB2 (Alimandi et al., experiments revealed that ErbB2 and ErbB3 function 1995; Wallasch et al., 1995; Cohen et al., 1996a,b; Zhang together to stimulate mitogenic signaling networks. This in et al., 1996). The enhanced transforming properties of turn contributes to uncontrolled tumor cell proliferation by cells expressing multiple ErbB receptors are presumably a mechanism involving deregulation of the G -S transition due to the diversity and signaling potency emanating from through modulation of the activation status of the essential ErbB receptor combinations. Such synergies have clear G -S regulator cyclin E-dependent kinase 2 (Cyclin E­ potential in terms of their impact on the deregulation of Cdk2; Neve et al., 2000). The basis of this deregulation cellular proliferation associated with tumor progression. was demonstrated to be tumor cell dependency on elevated Overexpression of ErbB2 is observed in a significant ErbB2-ErbB3 receptor signaling for the maintenance of proportion of breast and ovarian cancers, where it is proteins involved in the sequestration of the Cdk2 inhibitor Ki associated with poor prognosis (Slamon et al., 1989). p27 pJ (see Sherr and Roberts, 1999 for overview of this ErbB2 overexpression triggers ligand-independent acti­ field). Loss of ErbB2-ErbB3 activity, therefore, leads to Ki vation of the kinase domain, apparently as a result of redirection of p27 pJ onto Cdk2 complexes, inhibiting its Ki spontaneous dimer formation. Although ErbB2 homo­ activity. A similar redirection of p27 pJ was also observed dimers alone may contribute to malignancy, a number of if ErbB2 receptor signaling was impeded using an anti­ observations suggest that ErbB2 does indeed cooperate ErbB2 growth inhibitory antibody (Lane et al., 2000), with other ErbB receptors during tumor development. confirming the role of ErbB2 receptor signaling in the Many human tumors that contain ErbB2 also exhibit potentiation of breast tumor cell proliferation through autocrine stimulation of ErbB 1 via expression of one of its deregulation of the G -S transition. numerous ligands (Salomon et al., 1995). Furthermore, mammary tumors derived from transgenic mice engin­ Erb82-dire cted therapies in the clinic eered to overexpress neu also exhibit co-overexpression of The ligand-independent activation of overexpressed endogenous ErbBl (DiGiovanna et al., 1998). The ability ErbB2, combined with its preferred role as a partner for of ErbB2 to potentiate ErbB 1 signaling, as discussed the other ErbB receptors, provides explanations for the above, would provide tumor cells with a more potent oncogenic potential of ErbB2 and its involvement in so growth stimulus and could lead to the activation of many human tumors. Considering the general importance additional intracellular pathways. Such cooperation of ErbB heterodimers and ErbB2 in particular, the latter would, therefore, contribute to the maintenance of has been under intense investigation as a target for cancer increased proliferation rates associated with tumor devel­ therapy. In this respect, a monoclonal antibody that targets opment. With this in mind, work from our own laboratory the extracellular domain of ErbB2 (known as 4D5) has shown that loss of ErbB2 function inhibits the specifically inhibits the in vitro growth of ErbB2-over­ proliferation of tumor cells displaying ErbB 1 autocrine expressing tumor cells (Hudziak et al., 1989; Lewis et al., activation (Jannot et al., 1996). 1993, 1996). Excitingly, the humanized version of this In terms of other receptor combinations, ErbB2 and antibody (Herceptin ) has been validated in the clinic as ErbB4 are also co-expressed in >50% of childhood an ErbB2-directed therapeutic approach (Baselga et al., medulloblastomas, and the ErbB4 ligand NRG-1 is 1996; Pegram et al., 1998; Cobleigh et al., 1999). found in a significant proportion of these same tumors. Moreover, this antibody is now being used to treat The simultaneous expression of all three appears to be of metastatic breast cancer patients with tumors overexpres­ biological significance for the malignancy (Gilbertson sing ErbB2. We have recently shown that treatment of et al., 1997), suggesting that co-expression of ErbB2 with ErbB2-overexpressing breast tumor cells with 4D5 results ErbB4 can enhance the effects of autocrine or paracrine in a rapid reduction of ErbB2 phosphorylation, suggesting NRG-1 signaling. inhibition of ErbB2 receptor signaling (Lane et al., 2000). However, through comparison of a growth-inhibited cell The Erb8 2-Erb 83 signaling moiety in cancer line with a cell line unaffected by 4D5 treatment, receptor Another important observation pertaining to ErbB hetero­ dephosphorylation was found to occur in both cases, whilst dimer collaboration during tumor development is that downstream effects were observed only in the case of the expression of ErbB3 is seen in many of the same tumor 4D5-sensitive cells. Hence, we postulate that antibody­ types that overexpress ErbB2, including breast, bladder induced inhibition of ErbB2 receptor activity in over­ and melanomas (Lemoine et al., 1992; Rajkumar et al., expressing tumor cells does not necessarily predict cellular 1996; Bodey et al., 1997; Siegel et al., 1999). Furthermore, response to antibody treatment (Lane et al., 2000). This many ErbB2-overexpressing breast tumors display ele­ phenomenon correlates with the fact that although all vated levels of phosphotyrosine on ErbB3 (Alimandi et al., patients treated with Herceptin do have tumors exhibit­ 1995), probably as a result of spontaneous dimerization ing ErbB2 overexpression, not all respond to treatment with ErbB2. Moreover, mammary tumors of transgenic (Baselga et al., 1996; Pegram et al., 1998; Cobleigh et al., mice expressing transforming Neu mutants exhibit select­ 1999). From these data it is clear that the contribution of ive upregulation of ErbB3 expression and activity (Siegel other ErbB receptors should be taken into account for et al., 1999), suggesting that there might be a selective future evaluations of ErbB2 as a target for tumor therapy. advantage/pressure leading to co-expression of both Through a clearer understanding of ErbB interactions, receptors. Indeed, our own experiments support this therefore, it is conceivable that future ErbB-directed viewpoint. Downregulation of membrane ErbB2 levels approaches may prove to be even more beneficial for in ErbB2-overexpressing breast tumor cells has been cancer treatment. 3164 The ErbB signaling network phospholipase C-yl with the activated EGF receptor. J. Biol. Chem., Acknowledgements 274, 26091-26097. Cobleigh,M.A. et al. (1999) Multinational study of the efficacy and Thanks to Dr Ali Badache for helpful comments on the review and to safety of humanized anti-HER2 monoclonal antibody in women who the other members of the laboratory for many stimulating discussions. have HER2-overexpressing metastatic breast cancer that has Dr Richard Neve was partially supported by a grant from the Krebsliga progressed after chemotherapy for metastatic disease. J. Clin. beider Basel. Dr Heidi Lane was partially supported by a grant from the Oncol., 17, 2639-2648. Sshweizerische Krebsliga. Cohen,B.D., Kiener,P.A., Green,J.M., Foy,L., Fell,P. and Zhang,K. (1996a) The relationship between human epidermal growth-like factor receptor expression and cellular transformation in N1H3T3 cells. J. Biol. Chem., 271, 30897-30903. References Cohen,B.D., Green,J.M., Foy,L. and Fell,H.P. (1996b) HER4-mediated biological and biochemical properties in N1H3T3 cells. J. Biol. Chem., Alimandi,M., Romano,A., Curia,M.C., Muraro,R., Fedi,P., 271, 4813-4818. Aaronson,S.A., Di Fiore,P.P. and Kraus,M.H. (1995) Cooperative Dankort,D.L., Wang,Z., Blackmore,V., Moran,M.F. and Muller,W.J. signaling of ErbB3 and ErbB2 in neoplastic transformation. (1997) Distinct tyrosine autophosphorylation sites negatively and Oncogene, 10, 1813-1821. positively modulate Neu-mediated transformation. Mol. Cell. Biol., Aroian,R.V., Koga,M., Mendel,J.E., Ohshima,Y. and Stemberg,P.W. 17, 541 0-5425. (1990) The let-23 gene necessary for Caenorhabditis elegans vulva! Darcy,K.M., Zangani,D., Wolhueter,A.L., Huang,R.Y., Vaughan,M.M., induction encodes a tyrosine kinase of the EGF receptor family. Russell,J.A. and Ip,M.M. (2000) Changes in ErbB2 (HER2/neu), Nature, 348, 693-699. ErbB3 and ErbB4 during growth, differentiation and apoptosis of Barbacci,E.G., Guarino,B.C., Stroh,J.G., Singleton,D.H., Rosnack,K.J., normal rat mammary epithelial cells. J. Histochem. Cyto chem., 48, Moyer,J.D. and Andrews,G.C. (1995) The structure basis for the 63-80. specificity of epidermal growth factor and heregulin binding. J. Biol. DiGiovanna,M.P., Lerman,M.A., Coffey,R.J., Muller,W.J., Cardiff,R.D. Chem., 270, 9585-9589. and Stem,D.F. (1998) Active signaling by Neu in transgenic mice. Bargmann,C.I., Hung,M.C. and Weinberg,R.A. (1986) Multiple Oncogene, 17, 1877- 1884. independent activations of the neu oncogene by a point mutation Downward,J., Parker,P. and Waterfield,M.D. (1984) Autophosphoryl­ altering the transmembrane domain of pl85. Cell, 45, 649-657. ation sites on the epidermal growth factor receptor. Nature, 311 , Baselga,J. et al. (1996) Phase II study of weekly intravenous 483-485. recombinant humanized anti-pl85HER2 monoclonal antibody in Elenius,K., Choi,C.J., Paul,S., Santiestevan,E., Nishi,E. and patients with HER2/neu-overexpressing metastatic breast cancer. J. Klagsbrun,M. (1999) Characterization of a naturally occurring Clin. Oncol., 14, 737-744. ErbB4 isoform that does not bind or activate phosphatidyl inositol Batzer,A.G., Rotin,D., Urena,J.M., Skolnik,E.Y. and Schlessinger,J. 3-kinase. Oncogene, 18, 2607-26 15. (1994) Hierarchy of binding sites for Grb2 and She on the epidermal Erickson,S.L., O' Shea,K.S., Ghaboosi,N., Loverro,L., Frantz,G., growth factor receptor. Mol. Cell. Biol., 14, 5192-520 1. Bauer,M., Lu,L.H. and Moore,M.W. (1997) ErbB3 is required for Baulida,J., Kraus,M.H., Alimandi,M., Di Fiore,P.P. and Carpenter,G. normal cerebellar and cardiac development: a comparison with (1996) All ErbB receptors other than the epidermal growth factor ErbB2-and heregulin-deficient mice. Development, 124, 4999-5011. receptor are endocytosis impaired. J. Biol. Chem., 271, 525 1-5257. Fazioli,F., Minichiello,L., Matoskova,B., Wong,W.T. and Di Fiore,P.P. Beerli,R.R. and Hynes,N.E. (1996) Epidermal growth factor-related (1993) Eps15, a novel tyrosine kinase substrate, exhibits transforming peptides activate distinct subsets of erbB receptors and differ in their activity. Mol. Cell. Biol., 13, 5814-5828. biological activities. J. Biol. Chem., 271, 607 1-6076. Fiddes,R.J., Campbell,D.H., Janes,P.W., Sivertsen,S.P., Sasaki,H., Beerli,R.R., Wels,W. and Hynes,N.E. (1994) Intracellular expression of Wallasch,C. and Daly,R.J. (1998) Analysis of Grb7 recruitment by single chain antibodies reverts ErbB-2 transformation. J. Biol. Chem., heregulin-activated erbB3 receptors reveals a novel target selectivity 269, 23931-23936. for erbB3. J. Biol. Chem., 273, 77 17-7724. Beerli,R.R., Graus-Porta,D., Woods-Cook,K., Chen,X., Yarden,Y. and Fowler,K.J. et al. (1995) A mutation in the epidermal growth factor Hynes,N.E. (1995) Neu differentiation factor activation of ErbB-3 and receptor in waved-2 mice has a profound effect on receptor ErbB-4 is cell specific and displays a differential requirement for biochemistry that results in impaired lactation. Proc. Natl Acad. Sci. ErbB-2. Mol. Cell. Biol., 15, 6496--6505. USA, 92, 1465-14 69. Biscardi,J.S., Maa,M.C., Tice,D.A., Cox,M.E., Leu,T.H. and Parsons,S.J. French,A.R., Tadaki,D.K., Niyogi,S.K. and Lauffenb urger,D.A. (1995) (1999a) c-Src-mediated phosphorylation of the EGF receptor on Intracellular trafficking of epidermal growth factor family ligands is Tyr845 and Tyrl 101 is associated with modulation of receptor directly influenced by the pH sensitivity of the receptorffigand function. J. Biol. Chem., 274, 8335-8343. Biscardi,J.S., Tice,D.A. and Parsons,S.J. (1999b) c-Src, receptor tyrosine interaction. J. Biol. Chem., 270, 4334-4340. kinases and human cancer. Adv. Cancer Res., 76, 61-1 17. Gassmann,M., Casagranda,F., Orioli,D., Simon,H., Lai,C., Klein,R. and Lemke,G. (1995) Aberrant neural and cardiac development in mice Bodey,B., Bodey,B.,Jr, Groger,A.M., Luck,J.V., Siegel,S.E., Taylor,C.R. lacking the erbB4 neuregulin receptor. Nature, 378, 390-394. and Kaiser,H.E. (1997) Clinical and prognostic significance of the Gilbertson,R.J., Perry,R.H., Kelly,P.J., Pearson,A.D.J. and Lunee,J. expression of the c-erbB-2 and c-erbB-3 oncoproteins in primary and (1997) Prognostic significance of HER2 and HER4 co-expression in metastatic malignant melanomas and breast carcinomas. Anticancer childhood medulloblastoma. Cancer Res., 57, 3272-3280. Res., 17, 1319-1 330. Graus-Porta,D., Beerli,R.R. and Hynes,N.E. (1995) Single-chain Britsch,S., Li,L., Kirchhoff ,S., Theuring,F., Brinkmann,V., antibody-mediated intracellular retention of ErbB-2 impairs Neu Birchmeier,C. and Riethmacher,D. (1998) The ErbB2 and ErbB3 differentiation factor and epidermal growth factor signaling. Mol. Cell. receptors and their ligand, neuregulin- 1, are essential for development Biol., 15, 1182-1 191. of the sympathetic nervous system. Genes Dev., 12, 1825- 1836. Busfield,S.J. et al. (1997) Characterization of a neuregulin-related gene, Graus-Porta,D., Beerli,R.R., Daly,J.M. and Hynes,N.E. (1997) ErbB-2, Don- 1, that is highly expressed in restricted regions of the cerebellum the preferred heterodimerization partner of all ErbB receptors, is a and hippocampus. Mol. Cell. Biol., 17, 4007 -40 14 . mediator of lateral signaling. EMB O J. , 16, 1647-1655. Carpenter,G. (1999) Employment of the epidermal growth factor Groenen,L.C., Nice,E.C. and Burgess,A.W. (1994) Structure-function receptor in growth factor-independent signaling pathways. J. Cell relationships for the EGFtrGF-a family of mitogens. Growth Factors, Biol., 146, 697-702. 11, 235-257. Guy,P.M., Platko,J.V., Cantley,L.C., Cerione,R.A. and Carraway,K.L. Carraway,K.L.,m, Weber,J.L., Unger,M.J., Ledesma,J., Yu,N., (1994) Insect cell-expressed p18(Jllrb possesses an impaired tyrosine Gassmann,M. and Lai,K. (1997) Neuregulin-2, a new ligand of ErbB3/ErbB4-receptor tyrosine kinases. Nature, 387, 512-5 16. kinase activity. Proc. Natl Acad. Sci. USA, 91, 8132-8 136. Chang,H., Riese,D.J.,11, Gilbert,W., Stem,D.F. and McMahan,U.J. Hackel,P.O., Zwick,E., Prenzel,N. and Ullrich,A. (1999) Epidermal (1997) Ligands for ErbB-family receptors encoded by a neuregulin­ growth factor receptors: critical mediators of multiple receptor like gene. Nature, 387, 509-5 12. pathways. Curr. Opin. Cell Biol., 11, 184-18 9. Chattopadhyay,A., Vecchi,M., Ji,Q., Memaugh,R. and Carpenter,G. Harari,D., Tzahar,E., Romano,J., Shelly,M., Pierce,J.H., Andrews,G.C. (1999) The role of individual SH2 domains in mediating association of and Yarden,Y. (1999) Neuregulin-4: a novel growth factor that acts 3165 M.A.Ola io e et al. y y through the ErbB-4 receptor tyrosine kinase. Oncogene, 18, 2681- ErbB-1/EGF-receptor but not to other ErbB proteins. Oncogene, 12, 2689. 1117-1125. Levkowitz,G. et al. (1999) Ubiquitin ligase activity and tyrosine Hazan,R., Margolis,B., Dombalagian,M., Ullrich,A., Zilberstein,A. and phosphorylation underlie suppression of growth factor signaling by Schlessinger,J. (1990) Identification of autophosphorylation sites of c-Cbl/Sli-1. Mol. Cell, 4, 1029-1040. HER2/neu. Cell Growth Diff er., 1, 3-7. Lewis,G.D., Figari,I., Fendly,B., Wong,W.L., Carter,P., Gorman,C. and Heldin,C.-H. (1995) Dimerization of cell surface receptors in signal Shepard,H.M. (1993) Differential responses of human tumor cell lines transduction. Cell, 80, 213-223. 11ER2 to anti-p185 monoclonal antibodies. Cancer lmm unol. Hennighausen,L. and Robinson,G.W. (1998) Think globally, act locally: lm munother. , 37, 255-263. the making of a mouse mammary gland. Genes Dev., 12, 449--455. Lewis,G.D., Lofgren,J.A., McMurtrey,A.E., Hui jens,A., Fendly,B.M., Hsuan,J.J., Totty,N. and Waterfield,M.D. (1989) Identification of a novel Bauer,K.D. and Sliwkowski,M.X. (1996) Growth regulation of human autophosphorylation site (P4) on the epidermal growth factor receptor. breast and ovarian tumor cells by heregulin: evidence for the Biochem. J., 262, 659--663. requirement of ErbB2 as a critical component in mediating Hudziak,R.M., Lewis,G.D., Winget,M., Fendly,B.M., Shepard,H.M. and 11ER2 heregulin responsiveness. Cancer Res., 56, 1457-1465. Ullrich,A. (1989) pl8 5 monoclonal antibody has antiproliferative Luetteke,N.C., Qiu,T.H., Fenton,S.E., Troyer,K.L., Riedel,R.F., effects in vitro and sensitizes human breast tumor cells to tumor Chang,A. and Lee,D.C. (1999) Targeted inactivation of the EGF and necrosis factor. Mol. Cell. Biol., 9, 1165-1172. amphiregulin genes reveals distinct roles for EGF ligands in mouse Hynes,N.E. and Stem,D.F. (1994) The biology of erbB-2/neu/HER-2 and mammary gland development. Development, 126, 2739-2750. its role in cancer. Biochim. Biophys. Acta, 1198, 165-184. Luttrell,L.M., Daaka,Y. and Lefkowitz,R.J. (1999) Regulation of Jannot,C.B., Beerli,R.R., Mason,S., Gullick,W.J. and Hynes,N.E. (1996) tyrosine kinase cascades by G-protein coupled receptors. Curr. Intracellular expression of a single-chain antibody directed to the Opin. Cell Biol., 11, 177-183. EGFR leads to growth inhibition of tumor cells. Oncogene, 13, 275- Margolis,B.L., Lax,I., Kris,R., Dombalagian,M., Honegger,A.M., Howk,R., Givol,D., Ullrich,A. and Schlessinger,J. (1989) All Joazeiro,C.A.P., Wing,S.S., Huang,H.K., Leverson,J.D., Hunter,T. and autophosphrylation sites of epidermal growth factor (EGF) receptor Liu,Y.C. (1999) The tyrosine kinase negative regulator c-Cbl as a and HER2/neu are located in their carboxyl-terminal tails. RING-type, E2-dependent ubiquitin-protein ligase. Science, 286, 309- Identification of a novel site in EGF receptor. J. Biol. Ch em., 264, 10667-10671. Jones,F.E. and Stem,D.F. (1999) Expression of dominant-negative Massague,J. and Pandiella,A. (1993) Membrane anchored growth ErbB2 in the mammary gland of transgenic mice reveals a role in factors. Annu. Rev. Biochem., 62, 515-541. lobuloalveolar development and lactation. Oncogene, 18, 3481-3490. Meisner,H., Daga,A., Buxton,J., Femandez,B., Chawla,A., Banerjee,U. Jones,F.E.,Welte,T., Fu,X.Y. and Stem,D.F. (1999) ErbB4 signaling in and Czech,M.P. (1997) Interactions of Drosophila Cbl with epidermal the mammary gland is required for lobuloalveolar development and growth factor receptors and role of Cbl in R7 photoreceptor cell Stat5 activation during lactation. J. Cell Biol., 147, 77-87. development. Mol. Cell. Biol., 17, 2217-2225. Jones,J.Y., Akita,R.W. and Sliwkowski,M.X. (1999) Binding Meyer,D. and Birchmeier,C. (1995) Multiple essential functions of specificities and affinities of egf domains for ErbB receptors. FEBS neuregulin in development. Nature, 378, 386-390. Lett., 447, 227-231. Miettinen,P.J., Berger,J.E., Meneses,J., Phung,P., Pedersen,R.A., Karunagaran,D., Tzahar,E., Beerli,R.R., Chen,X., Graus-Porta,D., Werb,Z. and Derynk,R. (1995) Epithelial immaturity and multiorgan Ratzkin,B.J., Seger,R., Hynes,N.E. and Yarden,Y. (1996) ErbB-2 is failure in mice lacking epidermal growth factor receptor. Nature, 376, a common auxiliary subunit of NDF and EGF receptors: implications 337-341. for breast cancer. EMB O J., 15, 254--264. Morris,J.K., Weichun,L., Hauser,C., Marchuk,Y., Getman,D. and Katsuura,M. and Tanaka,S. (1989) Topographic analysis of human Lee,K.F. (1999) Rescue of the cardiac defect in ErbB2 mutant mice epidermal growth factor by monospecific antibodies and synthetic reveals essential roles of ErbB2 in peripheral nervous system peptides. J. Biochem., 106, 87-92. development. Neuron, 23, 273-283. Keilhack,H., Tenev,T., Nyakatura,E., Godovac-Zimmermann,J., Neve,R.M., Sutterliity,H., Pullen,N., Lane,H.A., Daly,J.M., Krek,W. and Nielsen,L., Seedorf,K. and Bohmer,F.D. (1998) Phosphotyrosine Hynes,N.E. (2000) Effects of oncogenic ErbB2 on G cell cycle 1173 mediates binding of the protein-tyrosine phosphatase SHP-1 to regulators in breast tumour cells. Oncogene, 19, 1647-1656. the epidermal growth factor receptor and attenuation of receptor Ojeda,J. and Ma,Y.J. (1999) Glial-neuronal interactions in the signaling. J. Biol. Chem. , 273, 24839-24846. neuroendocrine control of mammalian puberty: facilitatory effects of Kokai,Y., Myers,J.N., Wada,T., Brown,V.I., LeVea,C.M., Davis,J.G., gonadal steroids. J. Neur obiol., 40, 528-540. Dobashi,K. and Greene,M.I. (1989) Synergistic interaction of Okabayashi,Y., Kido,Y., Okutani,T., Sugamoto,Y., Sakaguchi,K. and p 185 -neu and the EGF receptor leads to transformation of rodent Kasuga,M. (1994) Tyrosine 1148 and 1173 of activated human fibroblasts. Cell, 58, 287-292. epidermal growth factor receptors are binding sites of She in intact Kramer,R., Bucay,B., Kane,D.J., Martin,L.E., Tarpley,J.E. and cells. J. Biol. Chem., 269, 18674--18678. Theill,L.E. (1996) Neuregulins with an lg-like domain are essential Okutani,T., Okabayashi,Y., Kido,Y., Sugimoto,Y., Sakaguchi,K., for mouse myocardial and neuronal development. Proc. Natl Acad. Matuoka,K., Takenawa,T. and Kasuga,M. (1994) Grb2/Ash binds Sci. USA, 93, 4833--4838. directly to tyrosines 1068 and 1086 and indirectly to tyrosine 1148 of Lane,H.A., Beuvink,I., Motoyama,A.B., Daly,J.M., Neve,R.M. and activated human epidermal growth factor receptor in intact cells. Hynes,N.E. (2000) ErbB2 potentiates breast tumor proliferation J. Biol. Chem., 269, 31310---31314. Ki 1 through modulation of p27 P /Cdk2 complex formation: receptor Olayioye,M.A., Graus-Porta,D., Beerli,R.R., Rohrer,J., Gay,B. and overexpression does not determine growth dependency. Mol. Cell. Hynes,N.E. (1998) ErbB-1 and ErbB-2 acquire distinct signaling Biol., 20, 3210---3223. properties dependent upon their dimerization partner. Mol. Cell. Biol., Lee,K.F., Simon,H., Chen,H., Bates,B., Hung,M.C. and Hauser,C. 18, 5042-5051. (1995) Requirement for neuregulin receptor erbB2 in neural and Olayioye,M.A., Beuvink,I., Horsch,K., Daly,J.M. and Hynes,N.E. (1999) cardiac development. Nature, 378, 394--398. ErbB receptor-induced activation of Stat transcription factors is Lemmon,M.A., Bu,Z., Ladbury,J.E., Zhou,M., Pinchasi,D., Lax,I., mediated by Src tyrosine kinases. J. Biol. Chem., 274, 17209-17218. Engelman,D.M. and Schlessinger,J. (1997) Two EGF molecules Paria,B.C., Elenius,K., Klagsbrun,M. and Dey,S.K. (1999) Heparin­ contribute additively to stabilization of the EGFR dimer. EMB O J., binding EGF-like growth factor interacts with mouse blastocysts 16, 281-294. independently of ErbB 1: a possible role for heparan sulfate Lemoine,N.R., Barnes,D.M., Hollywood,D.P., Hughes,C.M., Smith,P., proteoglycans and ErbB4 in blastocyst implantation. Development, Dublin,E., Prigent,S.A., Gullick,W.J. and Hurst,H.C. (1992) 126, 1997-2005. Expression of the c-erbB3 gene product in breast cancer. Br. J. Pegram,M.D. et al. (1998) Phase II study of receptor-enhanced Cancer, 66, 1116-1121. chemosensitivity using recombinant humanized anti-p185HER2/neu Lesa,G.M. and Stemberg,P.W. (1997) Positive and negative tissue­monoclonal antibody plus cisplatin in patients with HER2/neu­ specific signaling by a nematode epidermal growth factor receptor. overexpressing metastatic breast cancer refractory to chemotherapy Mol. Biol. Cell, 8, 779-793. treatment. J. Clin. Oncol., 16, 2659-2671. Levkowitz,G., Klapper,L.N., Tzahar,E., Freywald,A., Sela,M. and Peles,E. and Yarden,Y. (1993) Neu and its ligands: from an oncogene to Yarden,Y. (1996) Coupling of the c-Cbl protooncogene product to neural factors. BioEssays, 15, 815-824. 3166 The ErbB signal ing network Pinkas-Kramarski,R. et al. (1996) Diversification of Neu differentiation Threadgill,D.W. et al. (1995) Targeted disruption of mouse EGF factor and epidermal growth factor signaling by combinatorial receptor: effect of genetic background on mutant phenotype. Science, receptor interactions. EMB O J., 15, 2452-2467. 269, 230-234. Prigent,S.A. and Gullick, W. (1994) Identification of c-erbB-3 binding Torrisi,M.R., Lotti,L.V., Belleudi,F., Gradini,R., Salcini,A.E., sites for phosphatidylinositol 3' -kinase and SHC using an EGF Confalonieri, S., Pelicci,P.G. and Di Fiore,P.P. (1999) Eps15 is receptor/c-erbB-3 chimera. EMB O J., 13, 2831-2841. recruited to the plasma membrane upon epidermal growth factor Rajkumar,T., Stamp,G.W.H., Pandha,H.S., Waxman,J. and Gullick,W.J. receptor activation and localizes to components of the endocytic (1996) Expression of the type 1 tyrosine kinase growth factor EGF pathway during receptor internalization. Mol. Biol. Cell, 10, 417-434. receptors c-erbB-2 and c-erbB-3 in bladder cancer. J. Pathol., 179, Toyoda,H., Komurasaki,T., Uchida,D. and Morimoto,S. (1997) 381-385. Distribution of mRNA for human epiregulin, a differentially Ricci,A., Lanfrancone,L., Chiari,R., Belardo,G., Pertica,C., Natali,P.G., expressed member of the epidermal growth factor family. Biochem. Pelicci,P.G. and Segatto,O. (1995) Analysis of protein-protein J., 326, 69-75. interactions involved in the activation of the Shc/Grb-2 pathways by Tzahar,E., Waterman,H., Chen,X., Levkowitz,G., Karunagaran,D., the ErbB-2 kinase. Oncogene, 11, 1519-1529. Lavi,S., Ratzkin,B.J. and Yarden,Y. (1996) A hierarchical network Riese,D.J.,II and Stern,D.F. (1998) Specificity within the EGF family/ of interreceptor interactions determines signal transduction by Neu ErbB receptor family signaling network. BioEssays, 20, 41-48. differentiation factor/neuregulin and epidermal growth factor. Mol. Riese,D.J.,II, van Raaij,T.M., Plowman,G.D., Andrews,G.C. and Cell. Biol., 16, 5276--5287. Stern,D.F. (1995) The cellular response to neregulins is governed by Tzahar,E. et al. (1997) Bivalence of EGF-like ligands drives the ErbB complex interactions of the erbB receptor family. Mol. Cell. Biol., 15, signaling network. EMB O J., 16, 4938-4950. 5770-5776. Tzahar,E. et al. (1998) Pathogenic poxviruses reveal viral strategies to Riese,D.J.,II, Bermingham,Y., van Raaij,T.M., Buckley,S., exploit the ErbB signaling network. EMB O J., 17, 5948-5963. Plowrnan,G.D. and Stern,D.F. (1996) Betacellin activates the Wallasch,C., Weiss,F.U., Niederfellner,G., Jallal,B., Issing,W. and epidermal growth factor receptor and ErbB4 and induces cellular Ullrich,A. (1995) Heregulin-dependent regulation of HER2/neu response patterns distinct from those stimulated by epidermal growth oncogenic signaling by heterodimerization with HER3. EMB O J., factor or neuregulin-�. Oncogene, 12, 345-353. 14, 4267-4275. Riethmacher,D., Sonnenberg-Riethmacher,E., Brinkmann,V., Yamaai,T., Walton,G.M., Chen,W.S., Rosenfeld,M.G. and Gill,G.N. (1990) Lewin,G.R. and Birchneier,C. (1995) Severe neuropathies in mice with Analysis of deletions of the carboxyl terminus of the EGFR reveals targeted mutations in the erbB3 receptor. Nature, 389, 725-730. self-phosphorylation at tyrosine 992 and enhanced in vivo tyrosine Rotin,D. et al. (1992) SH2 domains prevent tyrosine phosphorylation of phosphorylation of cell substrates. J. Biol. Chem., 265, 1750-1754. the EGF receptor: identification of Tyr992 as the high-affinity binding Wasserman,J.D. and Freeman,M. (1997) Control of EGF receptor site for SH2 domains of phospholipase Cy. EMB O J., 11, 559-567. activation in Drosophila. Trends Cell Biol., 7, 431-436. Sakaguchi,K., Okabayashi,Y., Kido,Y., Kimura,S., Matsumura,Y., Waterman,H., Sabanai,I., Geiger,B. and Yarden,Y. (1998) Alternative Inushima,K. and Kasuga,M. (1998) She phosphotyrosine-binding intracellular routing of ErbB receptors may determine signaling domain dominantly interacts with epidermal growth factor receptors potency. J. Biol. Chem., 273, 13819-13827. and mediates ras activation in intact cells. Mol. End ocrinol., 12, 536-- Weiner,D.B., Liu,J., Cohen,J.A., Williams,W.V. and Greene,M.I. (1989) 543. A point mutation in the neu oncogene mimics ligand induction of Salomon,D.S., Brandt,R., Ciardiello,F. and Normanno,N. (1995) receptor aggregation. Nature, 339, 230-231. Epidermal growth factor-related peptides and their receptors in Weiss,A. and Schlessinger,J. (1998) Switching signals on or off by human malignancies. Crit. Rev. Oncol. Hemat ol. , 19, 183-232. receptor dimerization. Cell, 94, 277-280. Sato,K., Sato,A., Aoto,M. and Fukami,Y. (1995) c-Src phosphorylates Wiesen,J.F., Young,P., Werb,Z. and Cunha,G.R. (1999) Signaling EGF receptor on tyrosine 845. Biochem. Biophys. Res. Commun., 215, through the stromal epidermal growth factor receptor is necessary 1078-1087. for mammary ductal development. Development, 126, 335-344. Schroeder,J.A. and Lee,D.C. (1998) Dynamic expression and activation Xie,W., Paterson,A.J., Chin,E., Nabell,L.M. and Kudlow,J.E. (1997) of ERBB receptors in the developing mouse mammary gland. Cell Targeted expression of a dominant negative epidermal growth factor Growth Diff er., 9, 451-464. receptor in the mammary gland of transgenic mice inhibits pubertal Segatto,O., Lonardo,F., Pierce,J.H., Bottaro,D.P. and Di Fiore,P.P. mammary duct development. Mol. Endocr inol., 11, 1766--1781. (1990) The role of autophosphorylation in modulation of erbB-2 Yang,Y., Spitzer,E., Meyer,D., Sachs,M., Niemann,C., Hartmann,G., transforming function. New Biol., 2, 187-195. Weidner,K.M., Birchmeier,C. and Birchmeier,W. (1995) Sequential Sherr,C.J. and Roberts,J.M. (1999) CDK inhibitors: positive and requirement of hepatocyte growth factor and neuregulin in the negative regulators of G -phase progression. Genes Dev., 13, 1501- morphogenesis and differentiation of the mammary gland. J. Cell 1512. Biol., 131, 215-226. Shoelson,S.E. (1997) SH2 and PTB domain interactions in tyrosine Yokouchi,M., Kondo,T., Houghton,A., Bartkiewicz,M., Horne,W.C., kinase signal transduction. Curr. Opin. Chem. Biol., 1, 227-234. Zhang,H., Yoshimura,A. and Baron,R. (1999) Ligand-induced ubiquitination of the epidermal growth factor receptor involves the Sibilia,M. and Wagner,E.F. (1995) Strain-dependent epithelial defects in mice lacking the EGF receptor. Science, 269, 234--238. interaction of the c-Cbl RING finger and UbcH7. J. Biol. Chem., 274, Sibilia,M., Steinbach,J.P., Stingl,L., Aguzzi,A. and Wagner,E.F. (1998) 31707-31712. A strain-dependent postnatal neurodegeneration in mice lacking EGF Yoon,C.H., Lee,J., Jongeward,G.D. and Sternberg,P.W. (1995) receptor. EMB O J., 17, 719-731. Similarity of sli-1, a regulator of vulval development in C.elegans, Siegel,P.M., Ryan,E.D., Cardiff,R.D. and Muller,W. (1999) Elevated to the manunalian proto-oncogene c-Cbl. Science, 269, 1102-1105. expression of activated forms of Neu/ErbB-2 and ErbB-3 are involved Zhang,D. et al. (1997) Neuregulin-3 (NRG3): a novel neural tissue­ in the induction of mammary tumors in transgenic mice: implications enriched protein that binds and activates ErbB4. Proc. Natl Acad. Sci. for human breast cancer. EMB O J., 18, 2149-2164. USA, 94, 9562-9567. Slamon,D.J. et al. (1989) Studies of the HER-2/neu proto-oncogene in Zhang,K., Sun,J., Liu,N., Wen,D., Chang,D., Thomason,A. and human breast and ovarian cancer. Science, 244, 707-712. Yoshinaga,S.K. (1996) Transformation of NIH 3T3 cells by HER3 Spencer,K.S.R., Graus-Porta,D., Leng,J., Hynes,N.E. and Klemke,R.L. or HER4 receptors requires the presence of HERl and HER2. J. Biol. (2000) ErbB2 is necessary for induction of carcinoma cell invasion by Chem., 271, 3884--3890. ErbB family receptor tyrosine kinases. J. Cell Biol., 148, 385-397. Zrihan-Licht,S., Deng,B., Yarden,Y., McShan,G., Keydar,I. and Stover,D.R., Becker,M., Liebetanz,J. and Lydon,N.B. (1995) Src Avraham,H. (1998) Csk homologous kinase, a novel signaling phosphorylation of the epidermal growth factor receptor at novel molecule, directly associates with the activated ErbB-2 receptor in sites mediates receptor interaction with Src and p85a.. J. Biol. Chem., breast cancer cells and inhibits their proliferation. J. Biol. Chem., 273, 270, 15591-15597. 4065-4072. Sudol,M. (1998) From Src homology domains to other signaling modules: proposal of the 'protein recognition code'. Oncogene, 17, Received April JO, 2000; revised May 12, 2000; 1469-1474. accepted May 15, 2000 Tang,C.K. and Lippman,M.E. (1998) EGF family receptors and their ligands in human cancer. In O' Malley,B.W. (ed.), Hormones and Signaling, Vol. I. Academic Press, San Diego, CA, pp. 113-165. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The EMBO Journal Springer Journals

The ErbB signaling network: receptor heterodimerization in development and cancer

Download PDF
9 pages

Loading next page...
 
/lp/springer-journals/the-erbb-signaling-network-receptor-heterodimerization-in-development-Q0OPbPF5tM

References (135)

Publisher
Springer Journals
Copyright
Copyright © European Molecular Biology Organization 2000
ISSN
0261-4189
eISSN
1460-2075
DOI
10.1093/emboj/19.13.3159
Publisher site
See Article on Publisher Site

Abstract

The EMBO Journal Vol. 19 No.13 pp.3159-3167, 2000 NEW EMBO MEMBERS' REVIEW The ErbB signaling network: receptor heterodimerization in development and cancer differentiation. Moreover, deregulated expression of ErbB Monilola A.Olayioye, Richard M.Neve 1, receptors, in particular ErbB 1 and ErbB2, has been Heidi A.Lane and Nancy E.Hynes implicated in the development and malignancy of Friedrich Miescher Institute, PO Box 2543, CH-4002 Basel, numerous types of human cancers. The ErbB family has Switzerland evolved from a single ligand-receptor combination in Present address: UCSF, 505 Parnassus/Box 1270, San Francisco, Caenorhabditis elegans (Aroian et al., 1990), through CA 94143-1270, USA Drosophila with one receptor and four ligands Corresponding author (Wasserman and Freeman, 1997), to vertebrates, where e-mail: [email protected] four ErbB receptors bind multiple EGF-related ligands. Consequently, numerous ErbB homo- and heterodimer combinations are possible in vertebrates, suggesting that Keywords: breast cancer/EGF-related growth factors/ the ErbB receptor family has evolved to provide a high mammary gland development/receptor tyrosine kinases/ degree of signaling diversity; an event that may have been signal transduction cascades necessary for the development of metazoans. With this in mind, we have attempted, in this short review, not only to discuss generally individual ErbB receptors and their Introduction signaling potential but also to provide examples of specific ErbB heterodimers in signaling and development. Our Cells are continuously exposed to diverse stimuli ranging particular emphasis will be on their role in mammary from soluble endocrine and paracrine factors, to signaling gland biology, an organ in which the ErbB family and its molecules on neighboring cells. It is of great importance ligands are critically involved in development, differenti­ that these extracellular signals are correctly interpreted by ation and cancer. the cell, in order to achieve an appropriate developmental or proliferative response. Receptors of the tyrosine kinase family play pivotal roles in this process. By binding to The ErbB receptors in development specific peptide ligands they are able to integrate these external stimuli with internal signal transduction path­ The importance of ErbB receptors in development is ways, contributing in this fashion to the ability of the cell proven from the analysis of genetically modified mice. to respond correctly to its environment. In this review, we Indeed, null mutations in individual ErbB loci are lethal. will concentrate on the role of ErbB receptors as normal More specifically, depending upon the genetic background signal transducers and their contribution to the process of of the host, loss of ErbB 1 leads to embryonic or perinatal malignant transformation during tumor development. lethality with mice showing abnormalities in multiple ErbB proteins belong to subclass I of the superfamily of organs including the brain, skin, lung and gastrointestinal receptor tyrosine kinases (RTKs). There are four members tract (Miettinen et al., 1995; Sibilia and Wagner, 1995; of the ErbB family: epidermal growth factor (EGF) Threadgill et al., 1995; Sibilia et al., 1998). ErbB2 null receptor (also termed ErbB 1/HERl), ErbB2/Neu/HER2, mice die at midgestation (El0.5) due to trabeculae ErbB3/HER3 and ErbB4/HER4. We will refer to them, malformation in the heart (Lee et al., 1995), a phenotype henceforth, as the ErbB receptors. All family members that is shared by ErbB4 knockout mice (Gassmann et al., have in common an extracellular ligand-binding domain, a 1995). In addition, through genetic rescue of heart development via myocardial expression of an ErbB2 single membrane-spanning region and a cytoplasmic protein tyrosine kinase domain. A family of ligands, the transgene, a further role for ErbB2 in peripheral nervous EGF-related peptide growth factors, bind the extracellular system development has been demonstrated (Morris et al., domain of ErbB receptors leading to the formation of both 1999). In the case of ErbB3, most knockout mice die by homo- and heterodimers. Dimerization consequently E13.5, displaying normal heart trabeculation but defective stimulates the intrinsic tyrosine kinase activity of the valve formation. Additionally, these animals show a receptors and triggers autophosphorylation of specific generalized neural crest defect and lack Schwann cell tyrosine residues within the cytoplasmic domain. These precursors (Riethmacher et al., 1995; Erickson et al., phosphorylated residues serve as docking sites for signal­ 1997). From these data it is clear that ErbB receptors play ing molecules involved in the regulation of intracellular critical roles in modulating specific aspects of vertebrate signaling cascades. Ultimately, downstream effects on embryogenesis/development. gene expression determine the biological response to It is apparent, however, that ErbB receptors also play receptor activation. essential roles in the adult organism. The mammary gland ErbB receptors are expressed in a variety of tissues of is an organ that undergoes most of its proliferation and epithelial, mesenchymal and neuronal origin, where they differentiation postnatally. At birth, the gland has a play fundamental roles in development, proliferation and rudimentary system of ducts, which undergoes extensive © European Molecular Biology Organization 3159 M.A.Olayioye et al. development at puberty under the influence of steroid and BTC peptide hormones. During pregnancy, lobuloalveolar pro­ EGF NRG-I NRG -3 HB-EGF liferation occurs and, at parturition, the mammary fat pad LIGAND AR NRG-2 RG-4 EPR is completely filled with milk-producing lobuloalveolar TGFa units (Hennighausen and Robinson, 1998). In the mammary gland, all four ErbB receptors are expressed in cell type- and developmental stage-specific patterns (Schroeder and Lee, 1998; Darcy et al., 2000). Embryonic ... or early lethality has prevented direct analyses of mammary glands from ErbB receptor negative mice. However, other approaches have revealed the importance of functional ErbB receptors in this organ. In the case of rbB ErbBl, which is expressed at all stages of mammary gland RECEPTOR development, mice (wa-2) harboring a mutation in the ErbB 1 kinase domain exhibit sparse development of the mammary gland, indicative of defective ductal growth (Fowler et al., 1995). A major role for ErbBl in Fi . 1. Binding specificities of the EGF-related peptide growth factors. ductal growth was further confirmed by expression of There are four categories of ligands that bind ErbB family receptors. dominant-negative (DN) ErbB 1 in the mammary gland EGF, AR and TGFa bind ErbBl; BTC, HB-EGF and EPR bind ErbBI (Xie et al., 1997), as well as by reconstitution experiments and ErbB4; NRG-I and NRG-2 bind ErbB3 and ErbB4; and NRG-3 1 and NRG-4 bind ErbB4. See the text for more details. with ErbB1- - neonatal mammary glands (Wiesen et al., 1999). In contrast, despite the fact that ErbB2 is also expressed at all developmental stages, transgenics express­ and glial growth factor, reflecting the different biological ing DN ErbB2 in the mammary gland display normal ductal growth. These mice do appear, however, to have systems in which this ligand was first described (see Peles defective lobuloalveoli and reduced milk protein secretion and Yarden, 1993). Despite the large number of ligands so (Jones and Stem, 1999). As with ErbB2, transgenics far identified for ErbBl, 3 and 4, as well as intensive expressing DN ErbB4 in the mammary gland exhibit efforts, no direct ligand for ErbB2 has yet been discovered. normal ductal growth but impaired lactation (F. E.Jones However, increasing evidence suggests that the primary et al., 1999). Consequently, a role in lactation has also function of ErbB2 is as a coreceptor. In fact, ErbB2 is the been suggested for ErbB4, correlating with its elevated preferred heterodimerization partner for all other ErbB expression during pregnancy and lactation. ErbB3 is also family members (Figure 2) (Tzahar et al., 1996; Graus­ expressed throughout development; however, a detailed Porta et al., 1997) and plays a role in the potentiation of analysis of its function has not been described. In ErbB receptor signaling (Beerli et al., 1995; Graus-Porta summary, these data clearly suggest that the major et al., 1995). function of ErbB 1 in mammary gland development is in promoting ductal growth, while ErbB2 and ErbB4 appear Controlled expression determines ErbB ligand to have key roles in lobuloalveolar differentiation and availability lactation. Signaling diversity emanating from the ErbB family is generated by the repertoire of ErbB ligands and the combinatorial properties of induced receptor dimers. With ErbB ligands the exception of EGF, which is found in many body fluids, ErbB receptors are activated by a number of ligands, ErbB ligands generally act over short distances as referred to as EGF-related peptide growth factors autocrine or paracrine growth factors. The availability of (reviewed in Peles and Yarden, 1993; Riese and Stem, a specific ligand is, therefore, one way to control its 1998). These are produced as transmembrane precursors, signaling ability. In this respect, ErbB ligands demonstrate and are processed and released by proteolysis (Massague distinct expression patterns that are organ- and develop­ and Pandiella, 1993). There are numerous ErbB-specific mental stage-specific. Some ligands, such as NRG-1, are ligands, summarized in Figure 1, each with an EGF-like widely expressed (Meyer and Birchmeier, 1995) while domain that is sufficient to confer binding specificity. others show more restricted expression profiles. For These include EGF, amphiregulin (AR) and transforming example, the pancreas has high amounts of NRG-4 growth factor-a (TGFa), which bind specifically to (Harari et al., 1999), NRG-3 expression is restricted to ErbBl, and betacellulin (BTC), heparin-binding EGF developing and adult nervous system (Zhang et al., 1997) (HB-EGF) and epiregulin (E PR), which exhibit dual and EPR is high in macrophages and placenta (Toyoda specificity in that they bind both ErbB 1 and ErbB4. The et al., 1997). An extreme example for highly controlled neuregulins (NRG) comprise the third ligand family. expression, both with respect to tissue and time, is NRG-1 and NRG-2 (Riese et al., 1995; Busfield et al., HB- EGF, which is induced in the uterine luminal 1997; Carraway et al., 1997; Chang et al., 1997) both bind epithelium solely at the site of blastocyst apposition 6- ErbB3 and ErbB4, whereas the more recent additions to 7 h prior to uterine implantation (Paria et al., 1999). the NRG family, NRG-3 (Zhang et al., 1997) and NRG-4 In the case of the mammary gland, ErbB 1 ligands and (Harari et al., 1999), bind ErbB4 but not ErbB3. It should NRG- I are co-expressed at various developmental stages be stated that NRG- I is also known as neu differentiation (Yang et al., 1995; Schroeder and Lee, 1998). In order to factor, heregulin, acetylcholine receptor-inducing activity investigate their functional role during mammary gland 3160 The ErbB signaling network BTC et al., 1998). This implies that low-affinity ligands may be IEGF u RG-1 RG-1 even more potent signal inducers than their high-affinity counterparts, a possibility that should be examined more thoroughly. A third property of ErbB ligand binding is the pH stability of the ligand-receptor interaction, which influences receptor trafficking. For example, ligands such as EGF, whose receptor interaction is relatively pH resistant, target ErbB 1 to lysosomes, whereas TGFa and NRG-1 readily dissociate from their respective receptors at endosomal pH, resulting in receptor recycling (French Fig. 2. ErbB2 is the preferred dimerization partner for the other ErbB et al., 1995; Waterman et al., 1998). Subsequent rerouting receptors. Ligand binding to ErbBI (EGF), ErbB3 (NRG-I) or ErbB4 (NRG-I, BTC) induces the formation of receptor homodimers and of the receptor to the plasma membrane may, therefore, ErbB2-containing heterodimers. ErbB3 homodimers do not signal play a major role in signal potentiation. These ligand­ (indicated by the X), since the receptor has impaired kinase activity. specific characteristics provide an extra level of control, Only some of the possible ligand-receptor-induced combinations are contributing to the diversity and fine-tuning of cellular indicated in the figure for the sake of simplicity. responses to ErbB receptor activation. Such elaborate mechanisms reflect the importance of this receptor family in proliferation and differentiation. development, mice with individual targeted disruption of EGF, AR and TGFa, as well as triple null mice, have been generated (Luetteke et al., 1999). Analysis of these mice Major signaling pathways activated by ErbB has indicated that, while there is functional redundancy in receptors the roles of these ErbB ligands, some ligands make Overlapping and specific ErbB substrates specific contributions to mammary gland development. Ligand binding drives receptor dimerization, leading to For example, of the three ligands, AR expression is highest activation of the intrinsic tyrosine kinase and autophos­ in the developing ducts and only AR deficiency is phorylation of specific, C-terminal tyrosine residues associated with impaired ductal growth. This suggests (reviewed in Heldin, 1995; Weiss and Schlessinger, that AR plays an essential, non-redundant role in this 1998) that provide docking sites for proteins containing process. In contrast, however, lobuloalveolar development Src homology 2 (SH2) or phosphotyrosine binding (PTB) of lactating glands in AR null mice appears normal, domains (reviewed in Shoelson, 1997; Sudol, 1998). These whereas in triple null mice lactogenesis is abrogated include adaptor proteins such as She, Crk, Grb2, Grb7 and (Luetteke et al., 1999). Taken together, these data imply Gabl; kinases such as Src, Chk and phosphatidylinositol that functional differentiation of the mammary gland 3-kinase (PI3K; via the p85 regulatory subunit); and the requires the cooperation of multiple ErbB ligands. protein tyrosine phosphatases SHPl and SHP2. Each ErbB receptor displays a distinct pattern of C-terminal autophos­ Distinct biochemical properties of the ligands give phorylation sites. Examination of the binding preferences rise to signaling diversity of a variety of different SH2 and PTB domains, using Signaling diversity depends not only on the presence of a BioCore or phosphopeptide competition assays, combined specific ErbB receptor and its ligand, but also on the with studies utilizing receptor autophosphorylation site biochemical characteristics of the individual ErbB ligands. mutants and co-immunoprecipitation approaches, has First, ErbB ligands are bivalent, a property that determines enabled the identification of effector proteins that couple which receptor dimers are formed, thereby influencing the to specific ErbB phosphotyrosine residues (Figure 3). signaling pathways activated (Beerli and Hynes, 1996; From these analyses, it has become evident that there is a Riese et al., 1996). This biochemical feature bestows upon great deal of overlap in the signaling pathways activated the ligands, therefore, the ability to diversify signaling by the four ErbB receptors. Indeed, all ErbB family possibilities. Ligand bivalency has been implied from members, including the Drosophila and C.elegans homo­ biophysical (Lemmon et al., 1997), structure-function logs DER and Let23, couple via She and/or Grb2 to (Groenen et al., 1994) and immunological approaches the mitogen-activated protein (MAP) kinase pathway. (Katsuura and Tanaka, 1989). In the case ofNRG-1, using However, there are also examples of preferential modu­ a recombinant chimeric ligand (Barbacci et al., 1995; lation of specific pathways. For example, due to the Tzahar et al., 1997), it has been demonstrated that major presence of multiple binding sites for p85, ErbB3 is the determinants required for high-affinity binding to the most efficient activator of PI3K (Prigent and Gullick, primary ErbB receptor (ErbB3 or ErbB4) are contained 1994). In a similar vein, Eps15 and Cbl are examples of within the N-terminus, whilst the C-terminus recruits the ErbBl-specific substrates (Fazioli et al., 1993; Levkowitz second ErbB partner. The second partner is preferentially et al., 1996), both of which are involved in receptor ErbB2 (Tzahar et al., 1997), which has also been shown to downregulation. Eps15 binds the clathrin adaptor protein increase the affinity of ligand binding to all ErbB receptor complex AP-2 and participates in coated-pit-mediated heterodimers (J.Y.Jones et al., 1999). A second biochem­ internalization (Torrisi et al., 1999). Interestingly, in ical property of ErbB peptides is their differential binding contrast to other ErbB receptors, activated ErbB 1 is affinities, a characteristic that influences signal strength rapidly internalized via clathrin-mediated endocytosis and duration. In this respect, virally encoded, low-affinity (Baulida et al., 1996), a phenomenon perhaps related to ErbB-binding peptides have been demonstrated to hinder its specificity for Eps15. Moreover, Drosophila and normal receptor downregulation and degradation (Tzahar C.elegans Cbl orthologs are known to regulate RTK 3161 M.A.Ola io e et a/. y y ErbB4 ErbBJ ErbB2 ErbB3 ErbB-induced biological responses In order to assess the role of autophosphorylation sites in a specific response, individual tyrosine residues have been restored to ErbB mutants lacking the major autophos­ I!* phorylation sites. These are referred to as 'add-back' ll 7R mutants. This approach has mainly been used to examine llMO signaling from the Neu receptor, the rat ErbB2 equivalent. NeuT is the oncogenic variant of Neu, originally dis­ 1203/0S covered in rat neuroectodermal tumors. This mutant receptor possesses a single mutation that alters the 1 241 transmembrane domain (Bargmann et al., 1986), leading she 1 243 to constitutive receptor dimerization (Weiner et al., 1989). Mutation of NeuT autophosphorylation sites 1 2 5 7 she causes a dramatic reduction in its transforming ability. she she 1270 Surprisingly, four of the tyrosine residues when 'added she ehk back' individually fully restore the oncogenicity of NeuT. This demonstrates that, with respect to transformation potential, these tyrosines are functionally redundant Fig. 3. Specific phosphotyrosine residues and binding of signaling (Dankort et al., 1997). In contrast, analyses of transgenic molecules to the ErbB RTKs. ErbBl: tyrosine residues that have been identified as autophosphorylation sites (Downward et al., 1984; Hsuan nematodes expressing Let23 add-back mutants revealed et al., 1989; Margolis et al., 1989; Walton et al., 1990) (in yellow) and that individual tyrosines confer distinct biological func­ sites for the Src kinase (Stover et al., 1995) (in black), including Y845 tions. Viability and vulval differentiation were induced by in the T loop of the kinase domain (shown by an asterisk) (Sato et al., each of three tyrosine residues in a Ras-dependent manner, 1995; Biscardi et al., 1999a), are indicated. Some of the proteins that whereas a single tyrosine was sufficient to confer fertility have been shown to interact with specific tyrosine residues of ErbB 1 are indicated: She binds via its PTB domain to Y1173 and Y1148, and (Lesa and Sternberg, 1997). Comparison of the results via its SH2 domain to Y1173 (Batzer et al., 1994; Okabayashi et al., from these two analyses suggests that once multiple 1994; Sakaguchi et al., 1998); PLCy binds to Yl 173 (Chattopadhyay biological responses can be surveyed, more roles for et al., 1999) and Y992 (Rotin et al., 1992); the major and minor individual tyrosine residues and the pathways to which binding sites for Grb2 are, respectively, Y1068 and Y1086 (Batzer et al., 1994; Okutani et al., 1994); Cbl binds Y1045 (Levkowitz et al., they couple will be uncovered. 1999); SHP1 binds to Y1173 (Keilhack et al., 1998). ErbB2: tyrosine residues that have been identified as autophosphorylation sites are indicated (Hazan et al., 1990; Segatto et al., 1990). Proteins that have The power of ErbB receptor been shown to interact with specific tyrosine residues are indicated: heterodimerization She binds via its PTB domain to Yl 196 and Y1248, and via its SH2 domain to Y1248 and Y1221/2 (Ricci et al., 1995); the latter site has ErbB heterodimers provide signal diversification also been identified in Neu (Dankort et al., 1997); Grb2 binds Yl 139 The ability of ErbB ligands to induce not only receptor (Ricci et al., 1995) and the equivalent residue in Neu (Dankort et al., homodimers but also heterodimers expands ErbB signal­ 1997); Chk binds Y1248 (Zrihan-Licht et al., 1998). ErbB3: ing potential. Heterodimerization follows a strict hier­ phosphopeptide analyses of in viva labeled ErbB3 have not been published. The p85 subunit of PI3K and the She binding sites have archical principle with ErbB2 representing the preferred been mapped by phosphopeptide competition (Prigent and Gullick, dimerization partner of all other ErbB receptors (Figure 2) 1994). Peptides encompassing Y1035 and Y1270 compete strongly, (Tzahar et al., 1996; Graus-Porta et al., 1997). This peptides encompassing Y1178, Y1203/05, Y1241 and Y1257 compete phenomenon can be explained, as discussed above, by the less strongly for p85 binding; a peptide encompassing Y1309 competes for She binding. The major and minor sites for Grb7 binding are, binding preferences of the bivalent ligands. Thus, the ErbB respectively, Y1180 and Y1243 (Fiddes et al., 1998). ErbB4: dimers formed are dictated by the nature of the ligand and phosphopeptide analyses of in viva labeled ErbB4 have not been the cell's complement of ErbB receptors. ErbB2-contain­ published. Phosphopeptide competition analyses have shown that She ing heterodimers display increased ligand affinity due to a binds Y1242 and Yl 188 (Cohen et al., 1996b); the p85 subunit of decelerated off-rate (Karunagaran et al., 1996) that can be PI3K binds Y1056 (Elenius et al., 1999). (Only the cytoplasmic domains of the four ErbB RTKS are shown; for graphic purposes, the correlated with prolonged activation of downstream sig­ receptors have not been aligned.) naling pathways (Beerli et al., 1995; Graus-Porta et al., 1995). Furthermore, biological responses such as prolif­ eration (Beerli et al., 1995; Graus-Porta et al., 1995), signaling negatively (Yoon et al., 1995; Meisner et al., morphological differentiation (Beerli et al., 1995) and 1997); however, the mechanism by which this protein acts migration/invasion (Spencer et al., 2000) are enhanced in was only recently resolved. Cbl was identified as a RING cells expressing ErbB2. finger domain-containing E3 ubiquitin protein ligase ErbB heterodimerization is a means not only for signal (Joazeiro et al., 1999; Yokouchi et al., 1999), required amplification but also for signal diversification. The for ErbB 1 ubiquitylation and targeting of the receptor to subsets of SH2-and PTB-binding signaling molecules the lysosomal compartment (Levkowitz et al., 1999). recruited to an activated receptor are defined by the pattern These results help explain the dramatic decrease in ErbB 1 of phosphorylated tyrosine residues in the C-terminus of levels caused by ligand activation, something not observed the receptor (Figure 3). Based on our finding that the Cbl for the other ErbB receptors. Taken together, it is clear that protein coupled only to EGF- but not to NRG-activated ErbB receptors couple to specific downstream, intracel­ ErbB 1 (Graus-Porta et al., 1997), we speculated that signal lular pathways with differing efficiencies, thus affording diversification arises at one level by differential transphos­ greater signaling possibilities. phorylation of a given receptor in distinct ErbB dimers. By 3162 The ErbB signaling network phosphopeptide mapping of activated ErbB 1 and ErbB2 specific neuroendocrine sites. LHRH is essential for sexual from NIH 3T3 cells expressing single and pairwise development and adult reproductive function. In this combinations of ErbB receptors, we were able to prove respect, loss of ErbB2 function has been shown to delay that receptor phosphorylation is indeed modulated by the the onset of puberty, by preventing LHRH secretion, dimerization partner (Olayioye et al., 1998). This provides despite the continued presence of ErbB4 and NRG (Ojeda a biochemical explanation for the observation that EGF­ and Ma, 1999). ErbB receptor heterodimers, therefore, activated ErbBl, but not ErbBl heterodimerized with play significant roles in a number of developmental ErbB4, was able to recruit Grb2 (Olayioye et al., 1998). processes-roles that cannot be performed by homo­ Furthermore, despite similar levels of total phosphotyr­ dimers. This is indicative of the need to control receptor osine, ErbB2 constitutively dimerized due to a mutation in signaling precisely during development, and again reflects the transmembrane domain was considerably more potent the evolutionary diversification of this family of receptors in binding She than ErbB2 transactivated by EGF in metazoans. (Olayioye et al., 1998). Thus, the signal elicited by a receptor heterodimer is not simply the sum of the signaling ErbB receptors as signal integrators properties of the individual dimerization partners, but is In the past years it has become clear that there are also rather due to unique properties acquired by the hetero­ additional layers of complexity to the ErbB receptor dimer. For example, IL-3-dependent Ba/F3 cells engin­ system. For instance, ErbB RTKs integrate signaling eered to co-express ErbBl and ErbB4 demonstrate IL-3-events emanating from other receptor classes, such as independent proliferation in the presence of NDF or EGF. G-protein-coupled receptors and cytokine receptors. However, neither ligand promotes IL-3-independent pro­ Moreover, even in the absence of ErbB kinase activity, liferation of cells that individually express ErbB 1 or phosphorylation of specific residues in the cytoplasmic tail ErbB4 (Riese et al., 1996). Similarly, NRG-induced of the receptor by non-receptor kinases such as Jak and Src ErbB2- ErbB4 heterodimers activate the transcription can provide docking sites for cytoplasmic signaling factor Stat5 while homodimers of either receptor fail to molecules. Thus, in these cases, the receptor is simply do so (Olayioye et al., 1999). used as a scaffold protein, transmitting information to Continuing in this context, it should be noted that ErbB3 downstream signaling pathways. A detailed description of is an impaired kinase due to substitutions in critical these interactions is outside the scope of this article and residues in its kinase domain (Guy et al., 1994). Hence, the reader is referred to recent reviews on the different despite having multiple ligands, ErbB3 only functions as a modes of ErbB receptor activation (Biscardi et al., 1999b; signaling entity when complexed with another ErbB Carpenter, 1999; Hackel et al., 1999; Luttrell et al., 1999). receptor. Therefore, the process of ErbB heterodimeriza­ To date, most work in the area of signal transduction tion enables the integration of a ligand-less ErbB2 and a has concentrated on membrane-proximal events. Con­ kinase-defective ErbB3 into signal transduction processes. sequently, downstream effects on gene expression, result­ In fact, a consensus is emerging that the ErbB2- ErbB3 ing in the modulation of specific biological/developmental heterodimer is the most potent ErbB signaling complex in programs, are still scantily described. New technologies terms of in vitro growth and transformation (Alimandi such as nucleotide arrays and proteomics will help et al., 1995; Pinkas-Kramarski et al., 1996). elucidate the issue by providing more information on how ErbB receptor signaling impinges on the expression Biological effects of ErbB heterodimers of multiple genes and proteins. The ultimate goal will be to Phenotypes of ErbB receptor knock-out mice are the most understand the interplay of ErbB RTKs and their ligands in striking proof of the power of receptor heterodimers. Mice the context of the entire signaling network present in an individually null for ErbB2, ErbB4 or NRG-1 each organ. demonstrate a lack of trabeculae formation in the heart (Gassmann et al., 1995; Lee et al., 1995; Meyer and ErbB receptors in cancer: a special focus Birchmeier, 1995; Kramer et al., 1996), showing that an on ErbB cooperation important signaling moiety in the myocardium is the There is a wealth of clinical data demonstrating the ErbB2- ErbB4 heterodimer stimulated in a paracrine fashion by NRG-1. The essential contribution of this importance of ErbB receptors, in particular ErbB 1 and receptor collaboration to heart development is clearly ErbB2, in the development and malignancy of human observed in ErbB2 null mice, where NRG- I -induced cancer. However, considering the brevity and the theme of ErbB4 dimers cannot replace the function of the ErbB2- this review only examples of ErbB receptor synergy will ErbB4 heterodimer. Ligand-induced ErbB2- ErbB3 be discussed. The interested reader is referred to these heterodimers also play an important role in nervous system reviews (Hynes and Stem, 1994; Salomon et al., 1995; development. Indeed, mice individually mutant for ErbB2, Tang and Lippman, 1998) for more detailed information. ErbB3 or NRG-1 display a failure in neural crest cell Cooperation between ErbB receptors has been observed in migration, leading to impaired formation of the sympa­ oncogenic transformation, both in vitro in cultured cells thetic nervous system (Britsch et al., 1998). A further and in primary human tumors. Following the initial example of in vivo ErbB cooperation is provided by a observation that co-expression of ErbB2 with ErbB 1 in specific function for these receptors in the hypothalamus. NIH 3T3 fibroblasts augmented the effects of EGF on the Here, before the onset of puberty, NRG-mediated acti­ transformed phenotype (Kokai et al., 1989), there vation of ErbB2 and ErbB4 is required for the release of have been numerous studies on the collaboration of prostaglandin E2, which then controls the secretion of ErbB receptors in transformation. For example, ErbB3 luteinizing hormone-releasing hormone (LHRH) from expression increases ErbB2-mediated transformation and 3163 M.A.Ola io e et al. y y tumorigenic growth in NIH 3T3 cells. Also, NRG-1- achieved through the use of single-chain antibody (scFv) induced transformation of fibroblasts by ErbB4 requires technology (Beerli et al., 1994; Neve et al., 2000). These co-expression of either ErbB 1 or ErbB2 (Alimandi et al., experiments revealed that ErbB2 and ErbB3 function 1995; Wallasch et al., 1995; Cohen et al., 1996a,b; Zhang together to stimulate mitogenic signaling networks. This in et al., 1996). The enhanced transforming properties of turn contributes to uncontrolled tumor cell proliferation by cells expressing multiple ErbB receptors are presumably a mechanism involving deregulation of the G -S transition due to the diversity and signaling potency emanating from through modulation of the activation status of the essential ErbB receptor combinations. Such synergies have clear G -S regulator cyclin E-dependent kinase 2 (Cyclin E­ potential in terms of their impact on the deregulation of Cdk2; Neve et al., 2000). The basis of this deregulation cellular proliferation associated with tumor progression. was demonstrated to be tumor cell dependency on elevated Overexpression of ErbB2 is observed in a significant ErbB2-ErbB3 receptor signaling for the maintenance of proportion of breast and ovarian cancers, where it is proteins involved in the sequestration of the Cdk2 inhibitor Ki associated with poor prognosis (Slamon et al., 1989). p27 pJ (see Sherr and Roberts, 1999 for overview of this ErbB2 overexpression triggers ligand-independent acti­ field). Loss of ErbB2-ErbB3 activity, therefore, leads to Ki vation of the kinase domain, apparently as a result of redirection of p27 pJ onto Cdk2 complexes, inhibiting its Ki spontaneous dimer formation. Although ErbB2 homo­ activity. A similar redirection of p27 pJ was also observed dimers alone may contribute to malignancy, a number of if ErbB2 receptor signaling was impeded using an anti­ observations suggest that ErbB2 does indeed cooperate ErbB2 growth inhibitory antibody (Lane et al., 2000), with other ErbB receptors during tumor development. confirming the role of ErbB2 receptor signaling in the Many human tumors that contain ErbB2 also exhibit potentiation of breast tumor cell proliferation through autocrine stimulation of ErbB 1 via expression of one of its deregulation of the G -S transition. numerous ligands (Salomon et al., 1995). Furthermore, mammary tumors derived from transgenic mice engin­ Erb82-dire cted therapies in the clinic eered to overexpress neu also exhibit co-overexpression of The ligand-independent activation of overexpressed endogenous ErbBl (DiGiovanna et al., 1998). The ability ErbB2, combined with its preferred role as a partner for of ErbB2 to potentiate ErbB 1 signaling, as discussed the other ErbB receptors, provides explanations for the above, would provide tumor cells with a more potent oncogenic potential of ErbB2 and its involvement in so growth stimulus and could lead to the activation of many human tumors. Considering the general importance additional intracellular pathways. Such cooperation of ErbB heterodimers and ErbB2 in particular, the latter would, therefore, contribute to the maintenance of has been under intense investigation as a target for cancer increased proliferation rates associated with tumor devel­ therapy. In this respect, a monoclonal antibody that targets opment. With this in mind, work from our own laboratory the extracellular domain of ErbB2 (known as 4D5) has shown that loss of ErbB2 function inhibits the specifically inhibits the in vitro growth of ErbB2-over­ proliferation of tumor cells displaying ErbB 1 autocrine expressing tumor cells (Hudziak et al., 1989; Lewis et al., activation (Jannot et al., 1996). 1993, 1996). Excitingly, the humanized version of this In terms of other receptor combinations, ErbB2 and antibody (Herceptin ) has been validated in the clinic as ErbB4 are also co-expressed in >50% of childhood an ErbB2-directed therapeutic approach (Baselga et al., medulloblastomas, and the ErbB4 ligand NRG-1 is 1996; Pegram et al., 1998; Cobleigh et al., 1999). found in a significant proportion of these same tumors. Moreover, this antibody is now being used to treat The simultaneous expression of all three appears to be of metastatic breast cancer patients with tumors overexpres­ biological significance for the malignancy (Gilbertson sing ErbB2. We have recently shown that treatment of et al., 1997), suggesting that co-expression of ErbB2 with ErbB2-overexpressing breast tumor cells with 4D5 results ErbB4 can enhance the effects of autocrine or paracrine in a rapid reduction of ErbB2 phosphorylation, suggesting NRG-1 signaling. inhibition of ErbB2 receptor signaling (Lane et al., 2000). However, through comparison of a growth-inhibited cell The Erb8 2-Erb 83 signaling moiety in cancer line with a cell line unaffected by 4D5 treatment, receptor Another important observation pertaining to ErbB hetero­ dephosphorylation was found to occur in both cases, whilst dimer collaboration during tumor development is that downstream effects were observed only in the case of the expression of ErbB3 is seen in many of the same tumor 4D5-sensitive cells. Hence, we postulate that antibody­ types that overexpress ErbB2, including breast, bladder induced inhibition of ErbB2 receptor activity in over­ and melanomas (Lemoine et al., 1992; Rajkumar et al., expressing tumor cells does not necessarily predict cellular 1996; Bodey et al., 1997; Siegel et al., 1999). Furthermore, response to antibody treatment (Lane et al., 2000). This many ErbB2-overexpressing breast tumors display ele­ phenomenon correlates with the fact that although all vated levels of phosphotyrosine on ErbB3 (Alimandi et al., patients treated with Herceptin do have tumors exhibit­ 1995), probably as a result of spontaneous dimerization ing ErbB2 overexpression, not all respond to treatment with ErbB2. Moreover, mammary tumors of transgenic (Baselga et al., 1996; Pegram et al., 1998; Cobleigh et al., mice expressing transforming Neu mutants exhibit select­ 1999). From these data it is clear that the contribution of ive upregulation of ErbB3 expression and activity (Siegel other ErbB receptors should be taken into account for et al., 1999), suggesting that there might be a selective future evaluations of ErbB2 as a target for tumor therapy. advantage/pressure leading to co-expression of both Through a clearer understanding of ErbB interactions, receptors. Indeed, our own experiments support this therefore, it is conceivable that future ErbB-directed viewpoint. Downregulation of membrane ErbB2 levels approaches may prove to be even more beneficial for in ErbB2-overexpressing breast tumor cells has been cancer treatment. 3164 The ErbB signaling network phospholipase C-yl with the activated EGF receptor. J. Biol. Chem., Acknowledgements 274, 26091-26097. Cobleigh,M.A. et al. (1999) Multinational study of the efficacy and Thanks to Dr Ali Badache for helpful comments on the review and to safety of humanized anti-HER2 monoclonal antibody in women who the other members of the laboratory for many stimulating discussions. have HER2-overexpressing metastatic breast cancer that has Dr Richard Neve was partially supported by a grant from the Krebsliga progressed after chemotherapy for metastatic disease. J. Clin. beider Basel. Dr Heidi Lane was partially supported by a grant from the Oncol., 17, 2639-2648. Sshweizerische Krebsliga. Cohen,B.D., Kiener,P.A., Green,J.M., Foy,L., Fell,P. and Zhang,K. (1996a) The relationship between human epidermal growth-like factor receptor expression and cellular transformation in N1H3T3 cells. J. Biol. Chem., 271, 30897-30903. References Cohen,B.D., Green,J.M., Foy,L. and Fell,H.P. (1996b) HER4-mediated biological and biochemical properties in N1H3T3 cells. J. Biol. Chem., Alimandi,M., Romano,A., Curia,M.C., Muraro,R., Fedi,P., 271, 4813-4818. Aaronson,S.A., Di Fiore,P.P. and Kraus,M.H. (1995) Cooperative Dankort,D.L., Wang,Z., Blackmore,V., Moran,M.F. and Muller,W.J. signaling of ErbB3 and ErbB2 in neoplastic transformation. (1997) Distinct tyrosine autophosphorylation sites negatively and Oncogene, 10, 1813-1821. positively modulate Neu-mediated transformation. Mol. Cell. Biol., Aroian,R.V., Koga,M., Mendel,J.E., Ohshima,Y. and Stemberg,P.W. 17, 541 0-5425. (1990) The let-23 gene necessary for Caenorhabditis elegans vulva! Darcy,K.M., Zangani,D., Wolhueter,A.L., Huang,R.Y., Vaughan,M.M., induction encodes a tyrosine kinase of the EGF receptor family. Russell,J.A. and Ip,M.M. (2000) Changes in ErbB2 (HER2/neu), Nature, 348, 693-699. ErbB3 and ErbB4 during growth, differentiation and apoptosis of Barbacci,E.G., Guarino,B.C., Stroh,J.G., Singleton,D.H., Rosnack,K.J., normal rat mammary epithelial cells. J. Histochem. Cyto chem., 48, Moyer,J.D. and Andrews,G.C. (1995) The structure basis for the 63-80. specificity of epidermal growth factor and heregulin binding. J. Biol. DiGiovanna,M.P., Lerman,M.A., Coffey,R.J., Muller,W.J., Cardiff,R.D. Chem., 270, 9585-9589. and Stem,D.F. (1998) Active signaling by Neu in transgenic mice. Bargmann,C.I., Hung,M.C. and Weinberg,R.A. (1986) Multiple Oncogene, 17, 1877- 1884. independent activations of the neu oncogene by a point mutation Downward,J., Parker,P. and Waterfield,M.D. (1984) Autophosphoryl­ altering the transmembrane domain of pl85. Cell, 45, 649-657. ation sites on the epidermal growth factor receptor. Nature, 311 , Baselga,J. et al. (1996) Phase II study of weekly intravenous 483-485. recombinant humanized anti-pl85HER2 monoclonal antibody in Elenius,K., Choi,C.J., Paul,S., Santiestevan,E., Nishi,E. and patients with HER2/neu-overexpressing metastatic breast cancer. J. Klagsbrun,M. (1999) Characterization of a naturally occurring Clin. Oncol., 14, 737-744. ErbB4 isoform that does not bind or activate phosphatidyl inositol Batzer,A.G., Rotin,D., Urena,J.M., Skolnik,E.Y. and Schlessinger,J. 3-kinase. Oncogene, 18, 2607-26 15. (1994) Hierarchy of binding sites for Grb2 and She on the epidermal Erickson,S.L., O' Shea,K.S., Ghaboosi,N., Loverro,L., Frantz,G., growth factor receptor. Mol. Cell. Biol., 14, 5192-520 1. Bauer,M., Lu,L.H. and Moore,M.W. (1997) ErbB3 is required for Baulida,J., Kraus,M.H., Alimandi,M., Di Fiore,P.P. and Carpenter,G. normal cerebellar and cardiac development: a comparison with (1996) All ErbB receptors other than the epidermal growth factor ErbB2-and heregulin-deficient mice. Development, 124, 4999-5011. receptor are endocytosis impaired. J. Biol. Chem., 271, 525 1-5257. Fazioli,F., Minichiello,L., Matoskova,B., Wong,W.T. and Di Fiore,P.P. Beerli,R.R. and Hynes,N.E. (1996) Epidermal growth factor-related (1993) Eps15, a novel tyrosine kinase substrate, exhibits transforming peptides activate distinct subsets of erbB receptors and differ in their activity. Mol. Cell. Biol., 13, 5814-5828. biological activities. J. Biol. Chem., 271, 607 1-6076. Fiddes,R.J., Campbell,D.H., Janes,P.W., Sivertsen,S.P., Sasaki,H., Beerli,R.R., Wels,W. and Hynes,N.E. (1994) Intracellular expression of Wallasch,C. and Daly,R.J. (1998) Analysis of Grb7 recruitment by single chain antibodies reverts ErbB-2 transformation. J. Biol. Chem., heregulin-activated erbB3 receptors reveals a novel target selectivity 269, 23931-23936. for erbB3. J. Biol. Chem., 273, 77 17-7724. Beerli,R.R., Graus-Porta,D., Woods-Cook,K., Chen,X., Yarden,Y. and Fowler,K.J. et al. (1995) A mutation in the epidermal growth factor Hynes,N.E. (1995) Neu differentiation factor activation of ErbB-3 and receptor in waved-2 mice has a profound effect on receptor ErbB-4 is cell specific and displays a differential requirement for biochemistry that results in impaired lactation. Proc. Natl Acad. Sci. ErbB-2. Mol. Cell. Biol., 15, 6496--6505. USA, 92, 1465-14 69. Biscardi,J.S., Maa,M.C., Tice,D.A., Cox,M.E., Leu,T.H. and Parsons,S.J. French,A.R., Tadaki,D.K., Niyogi,S.K. and Lauffenb urger,D.A. (1995) (1999a) c-Src-mediated phosphorylation of the EGF receptor on Intracellular trafficking of epidermal growth factor family ligands is Tyr845 and Tyrl 101 is associated with modulation of receptor directly influenced by the pH sensitivity of the receptorffigand function. J. Biol. Chem., 274, 8335-8343. Biscardi,J.S., Tice,D.A. and Parsons,S.J. (1999b) c-Src, receptor tyrosine interaction. J. Biol. Chem., 270, 4334-4340. kinases and human cancer. Adv. Cancer Res., 76, 61-1 17. Gassmann,M., Casagranda,F., Orioli,D., Simon,H., Lai,C., Klein,R. and Lemke,G. (1995) Aberrant neural and cardiac development in mice Bodey,B., Bodey,B.,Jr, Groger,A.M., Luck,J.V., Siegel,S.E., Taylor,C.R. lacking the erbB4 neuregulin receptor. Nature, 378, 390-394. and Kaiser,H.E. (1997) Clinical and prognostic significance of the Gilbertson,R.J., Perry,R.H., Kelly,P.J., Pearson,A.D.J. and Lunee,J. expression of the c-erbB-2 and c-erbB-3 oncoproteins in primary and (1997) Prognostic significance of HER2 and HER4 co-expression in metastatic malignant melanomas and breast carcinomas. Anticancer childhood medulloblastoma. Cancer Res., 57, 3272-3280. Res., 17, 1319-1 330. Graus-Porta,D., Beerli,R.R. and Hynes,N.E. (1995) Single-chain Britsch,S., Li,L., Kirchhoff ,S., Theuring,F., Brinkmann,V., antibody-mediated intracellular retention of ErbB-2 impairs Neu Birchmeier,C. and Riethmacher,D. (1998) The ErbB2 and ErbB3 differentiation factor and epidermal growth factor signaling. Mol. Cell. receptors and their ligand, neuregulin- 1, are essential for development Biol., 15, 1182-1 191. of the sympathetic nervous system. Genes Dev., 12, 1825- 1836. Busfield,S.J. et al. (1997) Characterization of a neuregulin-related gene, Graus-Porta,D., Beerli,R.R., Daly,J.M. and Hynes,N.E. (1997) ErbB-2, Don- 1, that is highly expressed in restricted regions of the cerebellum the preferred heterodimerization partner of all ErbB receptors, is a and hippocampus. Mol. Cell. Biol., 17, 4007 -40 14 . mediator of lateral signaling. EMB O J. , 16, 1647-1655. Carpenter,G. (1999) Employment of the epidermal growth factor Groenen,L.C., Nice,E.C. and Burgess,A.W. (1994) Structure-function receptor in growth factor-independent signaling pathways. J. Cell relationships for the EGFtrGF-a family of mitogens. Growth Factors, Biol., 146, 697-702. 11, 235-257. Guy,P.M., Platko,J.V., Cantley,L.C., Cerione,R.A. and Carraway,K.L. Carraway,K.L.,m, Weber,J.L., Unger,M.J., Ledesma,J., Yu,N., (1994) Insect cell-expressed p18(Jllrb possesses an impaired tyrosine Gassmann,M. and Lai,K. (1997) Neuregulin-2, a new ligand of ErbB3/ErbB4-receptor tyrosine kinases. Nature, 387, 512-5 16. kinase activity. Proc. Natl Acad. Sci. USA, 91, 8132-8 136. Chang,H., Riese,D.J.,11, Gilbert,W., Stem,D.F. and McMahan,U.J. Hackel,P.O., Zwick,E., Prenzel,N. and Ullrich,A. (1999) Epidermal (1997) Ligands for ErbB-family receptors encoded by a neuregulin­ growth factor receptors: critical mediators of multiple receptor like gene. Nature, 387, 509-5 12. pathways. Curr. Opin. Cell Biol., 11, 184-18 9. Chattopadhyay,A., Vecchi,M., Ji,Q., Memaugh,R. and Carpenter,G. Harari,D., Tzahar,E., Romano,J., Shelly,M., Pierce,J.H., Andrews,G.C. (1999) The role of individual SH2 domains in mediating association of and Yarden,Y. (1999) Neuregulin-4: a novel growth factor that acts 3165 M.A.Ola io e et al. y y through the ErbB-4 receptor tyrosine kinase. Oncogene, 18, 2681- ErbB-1/EGF-receptor but not to other ErbB proteins. Oncogene, 12, 2689. 1117-1125. Levkowitz,G. et al. (1999) Ubiquitin ligase activity and tyrosine Hazan,R., Margolis,B., Dombalagian,M., Ullrich,A., Zilberstein,A. and phosphorylation underlie suppression of growth factor signaling by Schlessinger,J. (1990) Identification of autophosphorylation sites of c-Cbl/Sli-1. Mol. Cell, 4, 1029-1040. HER2/neu. Cell Growth Diff er., 1, 3-7. Lewis,G.D., Figari,I., Fendly,B., Wong,W.L., Carter,P., Gorman,C. and Heldin,C.-H. (1995) Dimerization of cell surface receptors in signal Shepard,H.M. (1993) Differential responses of human tumor cell lines transduction. Cell, 80, 213-223. 11ER2 to anti-p185 monoclonal antibodies. Cancer lmm unol. Hennighausen,L. and Robinson,G.W. (1998) Think globally, act locally: lm munother. , 37, 255-263. the making of a mouse mammary gland. Genes Dev., 12, 449--455. Lewis,G.D., Lofgren,J.A., McMurtrey,A.E., Hui jens,A., Fendly,B.M., Hsuan,J.J., Totty,N. and Waterfield,M.D. (1989) Identification of a novel Bauer,K.D. and Sliwkowski,M.X. (1996) Growth regulation of human autophosphorylation site (P4) on the epidermal growth factor receptor. breast and ovarian tumor cells by heregulin: evidence for the Biochem. J., 262, 659--663. requirement of ErbB2 as a critical component in mediating Hudziak,R.M., Lewis,G.D., Winget,M., Fendly,B.M., Shepard,H.M. and 11ER2 heregulin responsiveness. Cancer Res., 56, 1457-1465. Ullrich,A. (1989) pl8 5 monoclonal antibody has antiproliferative Luetteke,N.C., Qiu,T.H., Fenton,S.E., Troyer,K.L., Riedel,R.F., effects in vitro and sensitizes human breast tumor cells to tumor Chang,A. and Lee,D.C. (1999) Targeted inactivation of the EGF and necrosis factor. Mol. Cell. Biol., 9, 1165-1172. amphiregulin genes reveals distinct roles for EGF ligands in mouse Hynes,N.E. and Stem,D.F. (1994) The biology of erbB-2/neu/HER-2 and mammary gland development. Development, 126, 2739-2750. its role in cancer. Biochim. Biophys. Acta, 1198, 165-184. Luttrell,L.M., Daaka,Y. and Lefkowitz,R.J. (1999) Regulation of Jannot,C.B., Beerli,R.R., Mason,S., Gullick,W.J. and Hynes,N.E. (1996) tyrosine kinase cascades by G-protein coupled receptors. Curr. Intracellular expression of a single-chain antibody directed to the Opin. Cell Biol., 11, 177-183. EGFR leads to growth inhibition of tumor cells. Oncogene, 13, 275- Margolis,B.L., Lax,I., Kris,R., Dombalagian,M., Honegger,A.M., Howk,R., Givol,D., Ullrich,A. and Schlessinger,J. (1989) All Joazeiro,C.A.P., Wing,S.S., Huang,H.K., Leverson,J.D., Hunter,T. and autophosphrylation sites of epidermal growth factor (EGF) receptor Liu,Y.C. (1999) The tyrosine kinase negative regulator c-Cbl as a and HER2/neu are located in their carboxyl-terminal tails. RING-type, E2-dependent ubiquitin-protein ligase. Science, 286, 309- Identification of a novel site in EGF receptor. J. Biol. Ch em., 264, 10667-10671. Jones,F.E. and Stem,D.F. (1999) Expression of dominant-negative Massague,J. and Pandiella,A. (1993) Membrane anchored growth ErbB2 in the mammary gland of transgenic mice reveals a role in factors. Annu. Rev. Biochem., 62, 515-541. lobuloalveolar development and lactation. Oncogene, 18, 3481-3490. Meisner,H., Daga,A., Buxton,J., Femandez,B., Chawla,A., Banerjee,U. Jones,F.E.,Welte,T., Fu,X.Y. and Stem,D.F. (1999) ErbB4 signaling in and Czech,M.P. (1997) Interactions of Drosophila Cbl with epidermal the mammary gland is required for lobuloalveolar development and growth factor receptors and role of Cbl in R7 photoreceptor cell Stat5 activation during lactation. J. Cell Biol., 147, 77-87. development. Mol. Cell. Biol., 17, 2217-2225. Jones,J.Y., Akita,R.W. and Sliwkowski,M.X. (1999) Binding Meyer,D. and Birchmeier,C. (1995) Multiple essential functions of specificities and affinities of egf domains for ErbB receptors. FEBS neuregulin in development. Nature, 378, 386-390. Lett., 447, 227-231. Miettinen,P.J., Berger,J.E., Meneses,J., Phung,P., Pedersen,R.A., Karunagaran,D., Tzahar,E., Beerli,R.R., Chen,X., Graus-Porta,D., Werb,Z. and Derynk,R. (1995) Epithelial immaturity and multiorgan Ratzkin,B.J., Seger,R., Hynes,N.E. and Yarden,Y. (1996) ErbB-2 is failure in mice lacking epidermal growth factor receptor. Nature, 376, a common auxiliary subunit of NDF and EGF receptors: implications 337-341. for breast cancer. EMB O J., 15, 254--264. Morris,J.K., Weichun,L., Hauser,C., Marchuk,Y., Getman,D. and Katsuura,M. and Tanaka,S. (1989) Topographic analysis of human Lee,K.F. (1999) Rescue of the cardiac defect in ErbB2 mutant mice epidermal growth factor by monospecific antibodies and synthetic reveals essential roles of ErbB2 in peripheral nervous system peptides. J. Biochem., 106, 87-92. development. Neuron, 23, 273-283. Keilhack,H., Tenev,T., Nyakatura,E., Godovac-Zimmermann,J., Neve,R.M., Sutterliity,H., Pullen,N., Lane,H.A., Daly,J.M., Krek,W. and Nielsen,L., Seedorf,K. and Bohmer,F.D. (1998) Phosphotyrosine Hynes,N.E. (2000) Effects of oncogenic ErbB2 on G cell cycle 1173 mediates binding of the protein-tyrosine phosphatase SHP-1 to regulators in breast tumour cells. Oncogene, 19, 1647-1656. the epidermal growth factor receptor and attenuation of receptor Ojeda,J. and Ma,Y.J. (1999) Glial-neuronal interactions in the signaling. J. Biol. Chem. , 273, 24839-24846. neuroendocrine control of mammalian puberty: facilitatory effects of Kokai,Y., Myers,J.N., Wada,T., Brown,V.I., LeVea,C.M., Davis,J.G., gonadal steroids. J. Neur obiol., 40, 528-540. Dobashi,K. and Greene,M.I. (1989) Synergistic interaction of Okabayashi,Y., Kido,Y., Okutani,T., Sugamoto,Y., Sakaguchi,K. and p 185 -neu and the EGF receptor leads to transformation of rodent Kasuga,M. (1994) Tyrosine 1148 and 1173 of activated human fibroblasts. Cell, 58, 287-292. epidermal growth factor receptors are binding sites of She in intact Kramer,R., Bucay,B., Kane,D.J., Martin,L.E., Tarpley,J.E. and cells. J. Biol. Chem., 269, 18674--18678. Theill,L.E. (1996) Neuregulins with an lg-like domain are essential Okutani,T., Okabayashi,Y., Kido,Y., Sugimoto,Y., Sakaguchi,K., for mouse myocardial and neuronal development. Proc. Natl Acad. Matuoka,K., Takenawa,T. and Kasuga,M. (1994) Grb2/Ash binds Sci. USA, 93, 4833--4838. directly to tyrosines 1068 and 1086 and indirectly to tyrosine 1148 of Lane,H.A., Beuvink,I., Motoyama,A.B., Daly,J.M., Neve,R.M. and activated human epidermal growth factor receptor in intact cells. Hynes,N.E. (2000) ErbB2 potentiates breast tumor proliferation J. Biol. Chem., 269, 31310---31314. Ki 1 through modulation of p27 P /Cdk2 complex formation: receptor Olayioye,M.A., Graus-Porta,D., Beerli,R.R., Rohrer,J., Gay,B. and overexpression does not determine growth dependency. Mol. Cell. Hynes,N.E. (1998) ErbB-1 and ErbB-2 acquire distinct signaling Biol., 20, 3210---3223. properties dependent upon their dimerization partner. Mol. Cell. Biol., Lee,K.F., Simon,H., Chen,H., Bates,B., Hung,M.C. and Hauser,C. 18, 5042-5051. (1995) Requirement for neuregulin receptor erbB2 in neural and Olayioye,M.A., Beuvink,I., Horsch,K., Daly,J.M. and Hynes,N.E. (1999) cardiac development. Nature, 378, 394--398. ErbB receptor-induced activation of Stat transcription factors is Lemmon,M.A., Bu,Z., Ladbury,J.E., Zhou,M., Pinchasi,D., Lax,I., mediated by Src tyrosine kinases. J. Biol. Chem., 274, 17209-17218. Engelman,D.M. and Schlessinger,J. (1997) Two EGF molecules Paria,B.C., Elenius,K., Klagsbrun,M. and Dey,S.K. (1999) Heparin­ contribute additively to stabilization of the EGFR dimer. EMB O J., binding EGF-like growth factor interacts with mouse blastocysts 16, 281-294. independently of ErbB 1: a possible role for heparan sulfate Lemoine,N.R., Barnes,D.M., Hollywood,D.P., Hughes,C.M., Smith,P., proteoglycans and ErbB4 in blastocyst implantation. Development, Dublin,E., Prigent,S.A., Gullick,W.J. and Hurst,H.C. (1992) 126, 1997-2005. Expression of the c-erbB3 gene product in breast cancer. Br. J. Pegram,M.D. et al. (1998) Phase II study of receptor-enhanced Cancer, 66, 1116-1121. chemosensitivity using recombinant humanized anti-p185HER2/neu Lesa,G.M. and Stemberg,P.W. (1997) Positive and negative tissue­monoclonal antibody plus cisplatin in patients with HER2/neu­ specific signaling by a nematode epidermal growth factor receptor. overexpressing metastatic breast cancer refractory to chemotherapy Mol. Biol. Cell, 8, 779-793. treatment. J. Clin. Oncol., 16, 2659-2671. Levkowitz,G., Klapper,L.N., Tzahar,E., Freywald,A., Sela,M. and Peles,E. and Yarden,Y. (1993) Neu and its ligands: from an oncogene to Yarden,Y. (1996) Coupling of the c-Cbl protooncogene product to neural factors. BioEssays, 15, 815-824. 3166 The ErbB signal ing network Pinkas-Kramarski,R. et al. (1996) Diversification of Neu differentiation Threadgill,D.W. et al. (1995) Targeted disruption of mouse EGF factor and epidermal growth factor signaling by combinatorial receptor: effect of genetic background on mutant phenotype. Science, receptor interactions. EMB O J., 15, 2452-2467. 269, 230-234. Prigent,S.A. and Gullick, W. (1994) Identification of c-erbB-3 binding Torrisi,M.R., Lotti,L.V., Belleudi,F., Gradini,R., Salcini,A.E., sites for phosphatidylinositol 3' -kinase and SHC using an EGF Confalonieri, S., Pelicci,P.G. and Di Fiore,P.P. (1999) Eps15 is receptor/c-erbB-3 chimera. EMB O J., 13, 2831-2841. recruited to the plasma membrane upon epidermal growth factor Rajkumar,T., Stamp,G.W.H., Pandha,H.S., Waxman,J. and Gullick,W.J. receptor activation and localizes to components of the endocytic (1996) Expression of the type 1 tyrosine kinase growth factor EGF pathway during receptor internalization. Mol. Biol. Cell, 10, 417-434. receptors c-erbB-2 and c-erbB-3 in bladder cancer. J. Pathol., 179, Toyoda,H., Komurasaki,T., Uchida,D. and Morimoto,S. (1997) 381-385. Distribution of mRNA for human epiregulin, a differentially Ricci,A., Lanfrancone,L., Chiari,R., Belardo,G., Pertica,C., Natali,P.G., expressed member of the epidermal growth factor family. Biochem. Pelicci,P.G. and Segatto,O. (1995) Analysis of protein-protein J., 326, 69-75. interactions involved in the activation of the Shc/Grb-2 pathways by Tzahar,E., Waterman,H., Chen,X., Levkowitz,G., Karunagaran,D., the ErbB-2 kinase. Oncogene, 11, 1519-1529. Lavi,S., Ratzkin,B.J. and Yarden,Y. (1996) A hierarchical network Riese,D.J.,II and Stern,D.F. (1998) Specificity within the EGF family/ of interreceptor interactions determines signal transduction by Neu ErbB receptor family signaling network. BioEssays, 20, 41-48. differentiation factor/neuregulin and epidermal growth factor. Mol. Riese,D.J.,II, van Raaij,T.M., Plowman,G.D., Andrews,G.C. and Cell. Biol., 16, 5276--5287. Stern,D.F. (1995) The cellular response to neregulins is governed by Tzahar,E. et al. (1997) Bivalence of EGF-like ligands drives the ErbB complex interactions of the erbB receptor family. Mol. Cell. Biol., 15, signaling network. EMB O J., 16, 4938-4950. 5770-5776. Tzahar,E. et al. (1998) Pathogenic poxviruses reveal viral strategies to Riese,D.J.,II, Bermingham,Y., van Raaij,T.M., Buckley,S., exploit the ErbB signaling network. EMB O J., 17, 5948-5963. Plowrnan,G.D. and Stern,D.F. (1996) Betacellin activates the Wallasch,C., Weiss,F.U., Niederfellner,G., Jallal,B., Issing,W. and epidermal growth factor receptor and ErbB4 and induces cellular Ullrich,A. (1995) Heregulin-dependent regulation of HER2/neu response patterns distinct from those stimulated by epidermal growth oncogenic signaling by heterodimerization with HER3. EMB O J., factor or neuregulin-�. Oncogene, 12, 345-353. 14, 4267-4275. Riethmacher,D., Sonnenberg-Riethmacher,E., Brinkmann,V., Yamaai,T., Walton,G.M., Chen,W.S., Rosenfeld,M.G. and Gill,G.N. (1990) Lewin,G.R. and Birchneier,C. (1995) Severe neuropathies in mice with Analysis of deletions of the carboxyl terminus of the EGFR reveals targeted mutations in the erbB3 receptor. Nature, 389, 725-730. self-phosphorylation at tyrosine 992 and enhanced in vivo tyrosine Rotin,D. et al. (1992) SH2 domains prevent tyrosine phosphorylation of phosphorylation of cell substrates. J. Biol. Chem., 265, 1750-1754. the EGF receptor: identification of Tyr992 as the high-affinity binding Wasserman,J.D. and Freeman,M. (1997) Control of EGF receptor site for SH2 domains of phospholipase Cy. EMB O J., 11, 559-567. activation in Drosophila. Trends Cell Biol., 7, 431-436. Sakaguchi,K., Okabayashi,Y., Kido,Y., Kimura,S., Matsumura,Y., Waterman,H., Sabanai,I., Geiger,B. and Yarden,Y. (1998) Alternative Inushima,K. and Kasuga,M. (1998) She phosphotyrosine-binding intracellular routing of ErbB receptors may determine signaling domain dominantly interacts with epidermal growth factor receptors potency. J. Biol. Chem., 273, 13819-13827. and mediates ras activation in intact cells. Mol. End ocrinol., 12, 536-- Weiner,D.B., Liu,J., Cohen,J.A., Williams,W.V. and Greene,M.I. (1989) 543. A point mutation in the neu oncogene mimics ligand induction of Salomon,D.S., Brandt,R., Ciardiello,F. and Normanno,N. (1995) receptor aggregation. Nature, 339, 230-231. Epidermal growth factor-related peptides and their receptors in Weiss,A. and Schlessinger,J. (1998) Switching signals on or off by human malignancies. Crit. Rev. Oncol. Hemat ol. , 19, 183-232. receptor dimerization. Cell, 94, 277-280. Sato,K., Sato,A., Aoto,M. and Fukami,Y. (1995) c-Src phosphorylates Wiesen,J.F., Young,P., Werb,Z. and Cunha,G.R. (1999) Signaling EGF receptor on tyrosine 845. Biochem. Biophys. Res. Commun., 215, through the stromal epidermal growth factor receptor is necessary 1078-1087. for mammary ductal development. Development, 126, 335-344. Schroeder,J.A. and Lee,D.C. (1998) Dynamic expression and activation Xie,W., Paterson,A.J., Chin,E., Nabell,L.M. and Kudlow,J.E. (1997) of ERBB receptors in the developing mouse mammary gland. Cell Targeted expression of a dominant negative epidermal growth factor Growth Diff er., 9, 451-464. receptor in the mammary gland of transgenic mice inhibits pubertal Segatto,O., Lonardo,F., Pierce,J.H., Bottaro,D.P. and Di Fiore,P.P. mammary duct development. Mol. Endocr inol., 11, 1766--1781. (1990) The role of autophosphorylation in modulation of erbB-2 Yang,Y., Spitzer,E., Meyer,D., Sachs,M., Niemann,C., Hartmann,G., transforming function. New Biol., 2, 187-195. Weidner,K.M., Birchmeier,C. and Birchmeier,W. (1995) Sequential Sherr,C.J. and Roberts,J.M. (1999) CDK inhibitors: positive and requirement of hepatocyte growth factor and neuregulin in the negative regulators of G -phase progression. Genes Dev., 13, 1501- morphogenesis and differentiation of the mammary gland. J. Cell 1512. Biol., 131, 215-226. Shoelson,S.E. (1997) SH2 and PTB domain interactions in tyrosine Yokouchi,M., Kondo,T., Houghton,A., Bartkiewicz,M., Horne,W.C., kinase signal transduction. Curr. Opin. Chem. Biol., 1, 227-234. Zhang,H., Yoshimura,A. and Baron,R. (1999) Ligand-induced ubiquitination of the epidermal growth factor receptor involves the Sibilia,M. and Wagner,E.F. (1995) Strain-dependent epithelial defects in mice lacking the EGF receptor. Science, 269, 234--238. interaction of the c-Cbl RING finger and UbcH7. J. Biol. Chem., 274, Sibilia,M., Steinbach,J.P., Stingl,L., Aguzzi,A. and Wagner,E.F. (1998) 31707-31712. A strain-dependent postnatal neurodegeneration in mice lacking EGF Yoon,C.H., Lee,J., Jongeward,G.D. and Sternberg,P.W. (1995) receptor. EMB O J., 17, 719-731. Similarity of sli-1, a regulator of vulval development in C.elegans, Siegel,P.M., Ryan,E.D., Cardiff,R.D. and Muller,W. (1999) Elevated to the manunalian proto-oncogene c-Cbl. Science, 269, 1102-1105. expression of activated forms of Neu/ErbB-2 and ErbB-3 are involved Zhang,D. et al. (1997) Neuregulin-3 (NRG3): a novel neural tissue­ in the induction of mammary tumors in transgenic mice: implications enriched protein that binds and activates ErbB4. Proc. Natl Acad. Sci. for human breast cancer. EMB O J., 18, 2149-2164. USA, 94, 9562-9567. Slamon,D.J. et al. (1989) Studies of the HER-2/neu proto-oncogene in Zhang,K., Sun,J., Liu,N., Wen,D., Chang,D., Thomason,A. and human breast and ovarian cancer. Science, 244, 707-712. Yoshinaga,S.K. (1996) Transformation of NIH 3T3 cells by HER3 Spencer,K.S.R., Graus-Porta,D., Leng,J., Hynes,N.E. and Klemke,R.L. or HER4 receptors requires the presence of HERl and HER2. J. Biol. (2000) ErbB2 is necessary for induction of carcinoma cell invasion by Chem., 271, 3884--3890. ErbB family receptor tyrosine kinases. J. Cell Biol., 148, 385-397. Zrihan-Licht,S., Deng,B., Yarden,Y., McShan,G., Keydar,I. and Stover,D.R., Becker,M., Liebetanz,J. and Lydon,N.B. (1995) Src Avraham,H. (1998) Csk homologous kinase, a novel signaling phosphorylation of the epidermal growth factor receptor at novel molecule, directly associates with the activated ErbB-2 receptor in sites mediates receptor interaction with Src and p85a.. J. Biol. Chem., breast cancer cells and inhibits their proliferation. J. Biol. Chem., 273, 270, 15591-15597. 4065-4072. Sudol,M. (1998) From Src homology domains to other signaling modules: proposal of the 'protein recognition code'. Oncogene, 17, Received April JO, 2000; revised May 12, 2000; 1469-1474. accepted May 15, 2000 Tang,C.K. and Lippman,M.E. (1998) EGF family receptors and their ligands in human cancer. In O' Malley,B.W. (ed.), Hormones and Signaling, Vol. I. Academic Press, San Diego, CA, pp. 113-165.

Journal

The EMBO Journal – Springer Journals

Published: Jul 3, 2000

Keywords: breast cancer; EGF‐related growth factors; mammary gland development; receptor tyrosine kinases; signal transduction cascades

There are no references for this article.