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Wnt Signaling: Multiple Pathways, Multiple Receptors, and Multiple Transcription Factors *

Wnt Signaling: Multiple Pathways, Multiple Receptors, and Multiple Transcription Factors * This paper is available online at www.jbc.org MINIREVIEW THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 281, NO. 32, pp. 22429 –22433, August 11, 2006 © 2006 by The American Society for Biochemistry and Molecular Biology, Inc. Printed in the U.S.A. include Axin, adenomatous polyposis coli (APC), and glyco- Wnt Signaling: Multiple gen synthase kinase 3 (GSK-3) keeps cytoplasmic levels of Pathways, Multiple Receptors, -catenin low through phosphorylation by GSK-3. Phosphoryl- ated -catenin becomes ubiquitylated and is targeted for deg- and Multiple Transcription radation by the proteasome (3). Following Wnt binding to a Factors receptor complex composed of members of the Frizzled (Fz) Published, JBC Papers in Press, June 22, 2006, DOI 10.1074/jbc.R600015200 family of seven transmembrane, serpentine receptors and low Michael D. Gordon and Roel Nusse density lipoprotein receptor-related protein (LRP), the From the Howard Hughes Medical Institute and Department of AxinAPCGSK-3 complex is inhibited, leading to a block in Developmental Biology, Stanford University School of Medicine, -catenin phosphorylation by GSK-3 (Fig. 1B). Hypophospho- Stanford, California 94305 rylated -catenin accumulates in the cytoplasm and is translo- Signaling pathways are an ever present force in every ani- cated to the nucleus where it regulates target gene expression mal’s life. During development, these pathways provide critical through partnerships with the T cell-specific transcription fac- cell-cell communication required to coordinate the activities of tor/lymphoid enhancer-binding factor 1 (TCF/LEF) family of transcription factors (4). vast numbers of cells. In adulthood, similar communication mechanisms are utilized to achieve tissue homeostasis and Wnt/Receptor Interactions regeneration. Regulation of signaling is crucial; too much or too little activity from a given signal transduction pathway can The role of Fz in acting as a receptor for Wnts is long estab- cause devastating results such as developmental defects or, lished; Fz carries an extracellular cysteine-rich domain that is later in life, disease. sufficient to bind Wnt proteins, and addition of Fz to Wnt non- The Wnts comprise a large family of highly conserved growth responsive cells can render signaling competence (5). However, factors that are responsible for important developmental and the discovery that members of the LRP family of single pass homeostatic processes throughout the animal kingdom (for a transmembrane proteins are also required for signal transduc- more comprehensive review see Ref. 1). Their implication in a tion immediately raised the possibility that Fz and LRP function wide array of developmental events and human diseases has made as co-receptors for Wnt proteins (6, 7). Indeed, binding has Wnts and their signaling pathways the subject of intense investi- been seen between Wnt and LRP, and a ternary complex gation over the last two decades. This has never been truer than in between a mouse Wnt and soluble forms of Fz and LRP extra- cellular domains has been reported (6). A model in which Wnt the past few years, when the association of Wnt signaling with physically mediates an interaction between Fz and LRP is there- stem cell fate has added fuel to an already active field. fore appealing. Is such an interaction sufficient to induce sig- Membership in the Wnt family is defined by amino acid naling in the absence of Wnt binding? Early reports suggest that sequence rather than functional properties. It is therefore not it is. Fusion of a heterologous ligand/receptor pair (NT3 and too surprising that Wnts have been associated with a number of TrkN) to Fz and LRP, respectively, is sufficient to induce Wnt- different activities and downstream signaling pathways. independent signaling when the two molecules are co-overex- Although the majority of work in the field to date has focused pressed, as is a fusion of a natural LRP-binding protein, Dick- on -catenin-dependent, or canonical, Wnt signaling, exam- kopf (DKK), to Fz (8, 9). Lastly, addition of the intracellular ples continue to accumulate in which Wnts and/or other key portion of LRP to the C terminus of Fz creates a constitutively components of the canonical signaling cascade participate in active receptor (10). These data argue that inducing the prox- -catenin-independent processes (reviewed in Ref. 2). In this imity of the Fz and LRP cytoplasmic domains is the key event in review, we will focus largely on the canonical pathway, paying Wnt signal initiation, although direct evidence of its occur- particular attention to recent insights. We will then touch on rence upon Wnt ligand reception has not yet been reported. some developments in -catenin-independent signaling and discuss some issues that may be important to all Wnts, regard- Signal Relay in the Cytoplasm less of the signal they generate. There has been much interest in elucidating the events that bridge the activation of the Fz/LRP receptors and inhibition of Wnt Signaling through -Catenin the -catenin destruction complex. A key intermediate in this The defining event in canonical Wnt signaling is the cyto- process is Dishevelled (Dsh), a cytosolic phosphoprotein plasmic accumulation of -catenin and its subsequent nuclear required upstream of AxinAPCGSK-3 inhibition in both fly translocation and activity (Fig. 1). Under unstimulated condi- tions, a -catenin destruction complex formed by proteins that The abbreviations used are: APC, adenomatous polyposis coli; GSK, glyco- gen synthase kinase; LRP, low density lipoprotein receptor-related protein; * This minireview will be reprinted in the 2006 Minireview Compendium, TCF, T cell-specific transcription factor; LEF, lymphoid enhancer-binding which will be available in January, 2007. factor 1; PCP, planar cell polarity; CE, convergence extension; RTK, receptor To whom correspondence should be addressed. Tel.: 650-723-7769; Fax: tyrosine kinase; CBP, CREB-binding protein; CREB, cAMP-response ele- 650-723-1399; E-mail: [email protected]. ment-binding protein. AUGUST 11, 2006• VOLUME 281 • NUMBER 32 JOURNAL OF BIOLOGICAL CHEMISTRY 22429 This is an Open Access article under the CC BY license. MINIREVIEW: Wnt Signaling and mammalian cells. Although Dishevelled’s requirement in ciation between Fz and Dsh or Wnt-dependent phosphoryla- Wnt signaling has been known for over a decade, the molecular tion of Dsh (11, 12). The kinases PAR-1 and CKII appear to events leading to Dsh activation by Frizzled and the manner in directly phosphorylate Dsh, although the precise role of each in which Dsh transduces the Wnt signal to the inhibitory complex transducing the Wnt signal is not entirely clear nor is the spe- have remained murky. Several papers report on a physical asso- cific activity bestowed on Dsh by phosphorylation (13). A second component that appears to play a key role in directly linking receptor activation to inhi- bition of the cytoplasmic -catenin destruction complex is a member of the complex itself, Axin. Once thought of as simply a scaffold pro- tein linking together other members of the complex, Axin now appears to play a more dynamic role in signal activation by binding directly to the cytoplasmic tail of LRP in response to Wnt reception (14). The recruit- ment of Axin to LRP is mediated by phosphorylation of LRP on key res- idues by the kinases CK1 and GSK-3 (15, 16). Surprisingly, over- expression of a membrane-tethered form of the LRP intracellular domain can induce -catenin accu- mulation, even in the absence of Fz or Dsh, suggesting that membrane recruitment of Axin is sufficient to activate signaling (17). Presumably this occurs through titration of Axin away from the AxinAPCGSK-3 complex, thereby compromising the ability of the complex to phos- phorylate -catenin. Nuclear Activity of -Catenin Once in the nucleus, -catenin partners with members of the LEF/ TCF family of transcription factors to activate the transcription of Wnt target genes (18, 19). TCF provides sequence-specific binding activity and, in the absence of nuclear -catenin, partners with the tran- scriptional repressor Groucho and histone deacetylases to form a repressive complex and block tran- FIGURE 1. An overview of canonical Wnt signaling. A, in cells not exposed to Wnt, -catenin associates with scription of Wnt target genes (20, and is phosphorylated by the destruction complex composed of Axin, APC, and GSK-3. Phosphorylated -cate- 21). When -catenin enters the nin is then targeted for degradation. At the same time, Wnt target genes are repressed by the association of TCF nucleus, it directly replaces Grou- with Groucho. B, Wnt binding to the Frizzled and LRP receptors induces phosphorylation of LRP and recruit- ment of Axin. Dsh is also phosphorylated, and the AxinAPCGSK-3 complex is inhibited, leading to accumula- cho from its binding of TCF and tion of cytosolic -catenin. Accumulated -catenin then translocates to the nucleus, replaces Groucho from converts the complex to a transcrip- TCF, and activates target genes. C, emerging details of the complexity of nuclear -catenin activity. In the classical canonical model, -catenin forms a complex with TCF and the transcription factors Brg1 and CBP. Lgs tional activator, thereby effecting and Pygo also bind to -catenin, possibly driving its nuclear localization in addition to playing a direct role in the transcription of Wnt target transcriptional activation. Negative regulation of signaling is provided by NLK (Nemo-like kinase), which phos- genes (22). Other members of this phorylates TCF, and ICAT (inhibitor of catenin) and Chibby, which are antagonists of -catenin. In addition to TCF, two other DNA-binding proteins have been shown to associate with -catenin: Pitx2 and Prop1 (center activating complex are the histone and right portion of panel). In the case of Prop1, -catenin can act as a transcriptional activator or repressor of acetylase CBP/p300 and the SWI/ specific genes, depending on the co-factors present. The participation of any particular -catenin complex in SNF complex member Brg-1, both transcriptional regulation is highly cell type-dependent. 22430 JOURNAL OF BIOLOGICAL CHEMISTRY VOLUME 281 • NUMBER 32 •AUGUST 11, 2006 MINIREVIEW: Wnt Signaling emerging complexity of -catenin nuclear activity may speak to one of the fundamental questions in the field, which is how different cell types respond to Wnt signaling by transcribing different (although often overlapping) sets of target genes. -Catenin-independent Signaling As its name denotes, the first fz gene described was not dis- covered for its role in Wnt signaling, but rather its function in organizing the bristles and hairs of the adult Drosophila cuticle (34). In flies mutant for fz, the normally uniform direction of hairs and bristles on the wings and thorax are perturbed, a result of disrupting what is now known as the planar cell polar- ity (PCP) pathway (reviewed in Ref. 35). In addition to Fz, another Wnt pathway component, Dsh, is also required for this process, and genetic analysis of the fly dsh gene has revealed mutations that separate its function in PCP and canonical Wnt signal transduction (36). Interestingly, mutations in the Dsh DEP (Dishevelled-Egl20-Pleckstrin) domain, which is abso- lutely required for PCP but dispensable for -catenin signaling, have also been found to affect the process of convergence extension (CE) in vertebrates (37, 38). CE is also disrupted by loss of function in vertebrate homologs of the dedicated PCP genes strabismus, flamingo, and prickle, suggesting that CE and PCP are controlled by homologous pathways (39). FIGURE 2. The many flavors of Wnt signaling. Wnts are known to associate All evidence in flies and vertebrates points toward a complete with a number of different cell surface receptors and produce a number of cellular outcomes. Binding to FrizzledLRP complex generates -catenin sig- separation of -catenin signaling and PCP signaling down- naling (center), whereas binding to the atypical RTK Ror2 can inhibit this activ- stream of Dsh. However, there is a long outstanding question of ity (bottom right). Additionally, certain Wnts can bind Ryk, another atypical what lies upstream of Fz in PCP, and more specifically, whether RTK, and elicit axon repulsion (left). The Wnt signaling components Frizzled and Dishevelled are involved in establishing PCP and controlling vertebrate it is a Wnt. There are no known Wnt gene mutations in the fly CE. The specific involvement of Wnts in these processes is unclear (see text). that disrupt PCP but mutations in the zebrafish wnt5 and/or Strikingly, although there are 19 Wnts in the mammalian genome, a single wnt11 genes cause CE phenotypes, suggesting that Wnts do act Wnt, Wnt5a, can participate in all of the processes shown here (excluding PCP), depending on the cell type and receptor complement present. as ligands in this system (37, 40). However, there is no direct evidence that Wnts act as directional cues in CE, rather than of which may act through the remodeling of chromatin sur- simply permissive signals. This is not to say that Wnts cannot rounding TCF binding sites (23, 24). act as directional cues; during the development of the verte- There are a number of other factors that bind to the TCF- brate and invertebrate central nervous system, sources or gra- catenin complex and are necessary for transcriptional activa- dients of Wnt protein can provide directional guidance to tion, including Legless (Lgs), Pygopus (Pygo), and most recently extending axons by transducing a signal through Ryk, an atyp- discovered hyrax/parafibromin, a member of the polymerase- ical member of the receptor tyrosine kinase (RTK) family associated factor 1 (PAF1) complex (25–28). Lgs and Pygo are (41–43). an intriguing pair of proteins that associate with -catenin in Just as PCP is most likely an example of Wnt-independent Fz the nucleus. Lgs binds directly to the N terminus of -catenin function, the association of Wnt and RTKs may illustrate a Fz- and serves as an adaptor to attach Pygo to the complex (25). independent function for Wnt (Fig. 2). Certain atypical mem- However, the essential function of Pygo is controversial; ini- bers of the RTK family have an extracellular Wnt binding tially thought of as a nuclear cofactor that enhances transcrip- domain, cysteine-rich domains in the case of Ror1 and Ror2 and tional activation by the TCF-catenin complex (25–27), a sub- a WIF (Wnt inhibitory factor) domain in the case of Ryk (44). sequent report suggested that Pygo affects transcription by The Drosophila homolog of Ryk, Derailed, is an axon guidance recruiting otherwise cytoplasmic -catenin to the nucleus (29), receptor that mediates repulsion from Wnt5 during embryonic a claim that has since been refuted in favor of the original model central nervous system patterning, a process that apparently (30). Additionally, the activity of TCF itself may be modulated does not involve Dsh or downstream canonical signaling com- by signaling from the mitogen-activated protein kinase cascade ponents (41). Similarly, a number of Wnts, including Wnt5a (a composed of TAK1 and NLK/Nemo (31), and TCF/LEF-inde- mammalian ortholog of Drosophila Wnt5), have been shown to pendent signaling by -catenin can occur through interactions act through Ryk as axon repellents during mammalian central with other DNA-binding proteins, including Pitx2 and Prop1 nervous system development (42). Whether the fly and mouse (32, 33). The latter case is further complicated by the observa- processes are homologous is not known, and an answer will tion that the Prop1-catenin complex can act both as an acti- require more detailed knowledge of the other protein compo- vator of transcription and also as a repressor, a function medi- nents mediating these signals. Moreover, Wnt5a can block ated by binding to the co-repressor Groucho (33). In all, the canonical signaling in a process that depends on another RTK, AUGUST 11, 2006• VOLUME 281 • NUMBER 32 JOURNAL OF BIOLOGICAL CHEMISTRY 22431 MINIREVIEW: Wnt Signaling Ror2 (45). Clearly, there is much work still to be done in defin- Second, evidence that mis-regulation of Wnt signaling is a con- ing the signal transduction pathways downstream of Wnt- tributing factor in a number of human diseases continues to binding RTKs and sorting out the specificities of each ligand/ accumulate. The most famous example is that of APC, muta- receptor(s) interaction in modulating axon guidance or tion of which causes familial adenomatous polyposis, a condi- -catenin stability. tion that inevitably leads to colorectal cancer (see Ref. 53). However, mutations in Wnts or Wnt signaling components Wnt Family History have been associated with diseases that cover a wide spectrum By reading even a cursory review such as this one, it is easy to of afflictions, from arthritis to schizophrenia (see Ref. 54). appreciate the enormous complexity of Wnt signaling. The Lastly, Wnts appear able to expand, or perhaps maintain, cer- large number and diversity of components utilized in transduc- tain undifferentiated stem cell populations (49). This observa- tion of Wnt signals is staggering and at least partially underlies tion has made Wnts more than just targets for understanding the specificity seen in the way a particular cell responds to a and potentially treating disease; Wnt proteins hold potential as given Wnt. How did Wnt signaling acquire such diversity and agents to manipulate multipotent cells in vitro and could pro- complexity? Part of the answer may come from the recent dis- vide a key element in developing stem cell-derived tissue covery that each Wnt gene has had a surprisingly large amount replacement therapies. of time to evolve independently of the others. Mammals have 19 Even as our understanding of the Wnt pathway continues to Wnt genes that, through phylogenetic analysis, can be placed expand, there are a number of important questions that remain. into 12 subfamilies (46, 47). The surprising observation is that In terms of signal transduction, the details of how signaling is these subfamilies are not the result of any recent evolutionary initiated upon Wnt binding to Fz and LRP need to be addressed diversification; at least 11 of these subfamilies are present in further, as does the mechanism by which the -catenin destruc- Cnidaria (specifically, the sea anemone Nematostella vectensis), tion complex is regulated. More daunting perhaps is the ques- a group that split from the last common ancestor of Bilaterians tion of how specificity is achieved in the nuclear activity of (chordates, flies, worms, etc.) very early in metazoan evolution -catenin and its regulation of target genes: How does cell iden- (48). This indicates that the acquisition of the Wnt subfamilies tity and the integration of other signals influence the set of was an early development in the evolution of metazoa and likely genes transcribed upon Wnt signal activation? Manipulating occurred about 650 million years ago (48). What was the reason this specificity using small molecules that target the proteins for early expansion of the Wnt family and its maintenance along involved could hold promise in treating specific disease pro- multiple disparate lineages over many millions of years? cesses. Additionally, as interest in using Wnt ligands in more The Wnt family’s long evolutionary history raises another therapeutic settings increases, it will be important to under- question: whether, aside from amino acid sequence similarity, stand more thoroughly the biochemical characteristics of these there are any universal properties of Wnts. The recent discov- proteins and the distinguishing characteristics of each family ery that Wnt proteins can be purified to homogeneity allows for member. Finally, it will be interesting to see whether we can some unique opportunities to address this issue and has already integrate the large amount of information we have on canonical raised one possible universal feature (49). Long known to be Wnt signaling with the increasing number of examples of poorly soluble in aqueous solution, it was discovered that Wnts -catenin-independent signaling. 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A., Lin, C., Gleiberman, A., Wang, J., Brault, V., Ruiz-Lozano, P., Genet. 5, 691–701 AUGUST 11, 2006• VOLUME 281 • NUMBER 32 JOURNAL OF BIOLOGICAL CHEMISTRY 22433 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Biological Chemistry American Society for Biochemistry and Molecular Biology

Wnt Signaling: Multiple Pathways, Multiple Receptors, and Multiple Transcription Factors *

Gordon, Michael D.; Nusse, Roel
Journal of Biological Chemistry , Volume 281 (32) – Aug 11, 2006
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10.1074/jbc.r600015200
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Abstract

This paper is available online at www.jbc.org MINIREVIEW THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 281, NO. 32, pp. 22429 –22433, August 11, 2006 © 2006 by The American Society for Biochemistry and Molecular Biology, Inc. Printed in the U.S.A. include Axin, adenomatous polyposis coli (APC), and glyco- Wnt Signaling: Multiple gen synthase kinase 3 (GSK-3) keeps cytoplasmic levels of Pathways, Multiple Receptors, -catenin low through phosphorylation by GSK-3. Phosphoryl- ated -catenin becomes ubiquitylated and is targeted for deg- and Multiple Transcription radation by the proteasome (3). Following Wnt binding to a Factors receptor complex composed of members of the Frizzled (Fz) Published, JBC Papers in Press, June 22, 2006, DOI 10.1074/jbc.R600015200 family of seven transmembrane, serpentine receptors and low Michael D. Gordon and Roel Nusse density lipoprotein receptor-related protein (LRP), the From the Howard Hughes Medical Institute and Department of AxinAPCGSK-3 complex is inhibited, leading to a block in Developmental Biology, Stanford University School of Medicine, -catenin phosphorylation by GSK-3 (Fig. 1B). Hypophospho- Stanford, California 94305 rylated -catenin accumulates in the cytoplasm and is translo- Signaling pathways are an ever present force in every ani- cated to the nucleus where it regulates target gene expression mal’s life. During development, these pathways provide critical through partnerships with the T cell-specific transcription fac- cell-cell communication required to coordinate the activities of tor/lymphoid enhancer-binding factor 1 (TCF/LEF) family of transcription factors (4). vast numbers of cells. In adulthood, similar communication mechanisms are utilized to achieve tissue homeostasis and Wnt/Receptor Interactions regeneration. Regulation of signaling is crucial; too much or too little activity from a given signal transduction pathway can The role of Fz in acting as a receptor for Wnts is long estab- cause devastating results such as developmental defects or, lished; Fz carries an extracellular cysteine-rich domain that is later in life, disease. sufficient to bind Wnt proteins, and addition of Fz to Wnt non- The Wnts comprise a large family of highly conserved growth responsive cells can render signaling competence (5). However, factors that are responsible for important developmental and the discovery that members of the LRP family of single pass homeostatic processes throughout the animal kingdom (for a transmembrane proteins are also required for signal transduc- more comprehensive review see Ref. 1). Their implication in a tion immediately raised the possibility that Fz and LRP function wide array of developmental events and human diseases has made as co-receptors for Wnt proteins (6, 7). Indeed, binding has Wnts and their signaling pathways the subject of intense investi- been seen between Wnt and LRP, and a ternary complex gation over the last two decades. This has never been truer than in between a mouse Wnt and soluble forms of Fz and LRP extra- cellular domains has been reported (6). A model in which Wnt the past few years, when the association of Wnt signaling with physically mediates an interaction between Fz and LRP is there- stem cell fate has added fuel to an already active field. fore appealing. Is such an interaction sufficient to induce sig- Membership in the Wnt family is defined by amino acid naling in the absence of Wnt binding? Early reports suggest that sequence rather than functional properties. It is therefore not it is. Fusion of a heterologous ligand/receptor pair (NT3 and too surprising that Wnts have been associated with a number of TrkN) to Fz and LRP, respectively, is sufficient to induce Wnt- different activities and downstream signaling pathways. independent signaling when the two molecules are co-overex- Although the majority of work in the field to date has focused pressed, as is a fusion of a natural LRP-binding protein, Dick- on -catenin-dependent, or canonical, Wnt signaling, exam- kopf (DKK), to Fz (8, 9). Lastly, addition of the intracellular ples continue to accumulate in which Wnts and/or other key portion of LRP to the C terminus of Fz creates a constitutively components of the canonical signaling cascade participate in active receptor (10). These data argue that inducing the prox- -catenin-independent processes (reviewed in Ref. 2). In this imity of the Fz and LRP cytoplasmic domains is the key event in review, we will focus largely on the canonical pathway, paying Wnt signal initiation, although direct evidence of its occur- particular attention to recent insights. We will then touch on rence upon Wnt ligand reception has not yet been reported. some developments in -catenin-independent signaling and discuss some issues that may be important to all Wnts, regard- Signal Relay in the Cytoplasm less of the signal they generate. There has been much interest in elucidating the events that bridge the activation of the Fz/LRP receptors and inhibition of Wnt Signaling through -Catenin the -catenin destruction complex. A key intermediate in this The defining event in canonical Wnt signaling is the cyto- process is Dishevelled (Dsh), a cytosolic phosphoprotein plasmic accumulation of -catenin and its subsequent nuclear required upstream of AxinAPCGSK-3 inhibition in both fly translocation and activity (Fig. 1). Under unstimulated condi- tions, a -catenin destruction complex formed by proteins that The abbreviations used are: APC, adenomatous polyposis coli; GSK, glyco- gen synthase kinase; LRP, low density lipoprotein receptor-related protein; * This minireview will be reprinted in the 2006 Minireview Compendium, TCF, T cell-specific transcription factor; LEF, lymphoid enhancer-binding which will be available in January, 2007. factor 1; PCP, planar cell polarity; CE, convergence extension; RTK, receptor To whom correspondence should be addressed. Tel.: 650-723-7769; Fax: tyrosine kinase; CBP, CREB-binding protein; CREB, cAMP-response ele- 650-723-1399; E-mail: [email protected]. ment-binding protein. AUGUST 11, 2006• VOLUME 281 • NUMBER 32 JOURNAL OF BIOLOGICAL CHEMISTRY 22429 This is an Open Access article under the CC BY license. MINIREVIEW: Wnt Signaling and mammalian cells. Although Dishevelled’s requirement in ciation between Fz and Dsh or Wnt-dependent phosphoryla- Wnt signaling has been known for over a decade, the molecular tion of Dsh (11, 12). The kinases PAR-1 and CKII appear to events leading to Dsh activation by Frizzled and the manner in directly phosphorylate Dsh, although the precise role of each in which Dsh transduces the Wnt signal to the inhibitory complex transducing the Wnt signal is not entirely clear nor is the spe- have remained murky. Several papers report on a physical asso- cific activity bestowed on Dsh by phosphorylation (13). A second component that appears to play a key role in directly linking receptor activation to inhi- bition of the cytoplasmic -catenin destruction complex is a member of the complex itself, Axin. Once thought of as simply a scaffold pro- tein linking together other members of the complex, Axin now appears to play a more dynamic role in signal activation by binding directly to the cytoplasmic tail of LRP in response to Wnt reception (14). The recruit- ment of Axin to LRP is mediated by phosphorylation of LRP on key res- idues by the kinases CK1 and GSK-3 (15, 16). Surprisingly, over- expression of a membrane-tethered form of the LRP intracellular domain can induce -catenin accu- mulation, even in the absence of Fz or Dsh, suggesting that membrane recruitment of Axin is sufficient to activate signaling (17). Presumably this occurs through titration of Axin away from the AxinAPCGSK-3 complex, thereby compromising the ability of the complex to phos- phorylate -catenin. Nuclear Activity of -Catenin Once in the nucleus, -catenin partners with members of the LEF/ TCF family of transcription factors to activate the transcription of Wnt target genes (18, 19). TCF provides sequence-specific binding activity and, in the absence of nuclear -catenin, partners with the tran- scriptional repressor Groucho and histone deacetylases to form a repressive complex and block tran- FIGURE 1. An overview of canonical Wnt signaling. A, in cells not exposed to Wnt, -catenin associates with scription of Wnt target genes (20, and is phosphorylated by the destruction complex composed of Axin, APC, and GSK-3. Phosphorylated -cate- 21). When -catenin enters the nin is then targeted for degradation. At the same time, Wnt target genes are repressed by the association of TCF nucleus, it directly replaces Grou- with Groucho. B, Wnt binding to the Frizzled and LRP receptors induces phosphorylation of LRP and recruit- ment of Axin. Dsh is also phosphorylated, and the AxinAPCGSK-3 complex is inhibited, leading to accumula- cho from its binding of TCF and tion of cytosolic -catenin. Accumulated -catenin then translocates to the nucleus, replaces Groucho from converts the complex to a transcrip- TCF, and activates target genes. C, emerging details of the complexity of nuclear -catenin activity. In the classical canonical model, -catenin forms a complex with TCF and the transcription factors Brg1 and CBP. Lgs tional activator, thereby effecting and Pygo also bind to -catenin, possibly driving its nuclear localization in addition to playing a direct role in the transcription of Wnt target transcriptional activation. Negative regulation of signaling is provided by NLK (Nemo-like kinase), which phos- genes (22). Other members of this phorylates TCF, and ICAT (inhibitor of catenin) and Chibby, which are antagonists of -catenin. In addition to TCF, two other DNA-binding proteins have been shown to associate with -catenin: Pitx2 and Prop1 (center activating complex are the histone and right portion of panel). In the case of Prop1, -catenin can act as a transcriptional activator or repressor of acetylase CBP/p300 and the SWI/ specific genes, depending on the co-factors present. The participation of any particular -catenin complex in SNF complex member Brg-1, both transcriptional regulation is highly cell type-dependent. 22430 JOURNAL OF BIOLOGICAL CHEMISTRY VOLUME 281 • NUMBER 32 •AUGUST 11, 2006 MINIREVIEW: Wnt Signaling emerging complexity of -catenin nuclear activity may speak to one of the fundamental questions in the field, which is how different cell types respond to Wnt signaling by transcribing different (although often overlapping) sets of target genes. -Catenin-independent Signaling As its name denotes, the first fz gene described was not dis- covered for its role in Wnt signaling, but rather its function in organizing the bristles and hairs of the adult Drosophila cuticle (34). In flies mutant for fz, the normally uniform direction of hairs and bristles on the wings and thorax are perturbed, a result of disrupting what is now known as the planar cell polar- ity (PCP) pathway (reviewed in Ref. 35). In addition to Fz, another Wnt pathway component, Dsh, is also required for this process, and genetic analysis of the fly dsh gene has revealed mutations that separate its function in PCP and canonical Wnt signal transduction (36). Interestingly, mutations in the Dsh DEP (Dishevelled-Egl20-Pleckstrin) domain, which is abso- lutely required for PCP but dispensable for -catenin signaling, have also been found to affect the process of convergence extension (CE) in vertebrates (37, 38). CE is also disrupted by loss of function in vertebrate homologs of the dedicated PCP genes strabismus, flamingo, and prickle, suggesting that CE and PCP are controlled by homologous pathways (39). FIGURE 2. The many flavors of Wnt signaling. Wnts are known to associate All evidence in flies and vertebrates points toward a complete with a number of different cell surface receptors and produce a number of cellular outcomes. Binding to FrizzledLRP complex generates -catenin sig- separation of -catenin signaling and PCP signaling down- naling (center), whereas binding to the atypical RTK Ror2 can inhibit this activ- stream of Dsh. However, there is a long outstanding question of ity (bottom right). Additionally, certain Wnts can bind Ryk, another atypical what lies upstream of Fz in PCP, and more specifically, whether RTK, and elicit axon repulsion (left). The Wnt signaling components Frizzled and Dishevelled are involved in establishing PCP and controlling vertebrate it is a Wnt. There are no known Wnt gene mutations in the fly CE. The specific involvement of Wnts in these processes is unclear (see text). that disrupt PCP but mutations in the zebrafish wnt5 and/or Strikingly, although there are 19 Wnts in the mammalian genome, a single wnt11 genes cause CE phenotypes, suggesting that Wnts do act Wnt, Wnt5a, can participate in all of the processes shown here (excluding PCP), depending on the cell type and receptor complement present. as ligands in this system (37, 40). However, there is no direct evidence that Wnts act as directional cues in CE, rather than of which may act through the remodeling of chromatin sur- simply permissive signals. This is not to say that Wnts cannot rounding TCF binding sites (23, 24). act as directional cues; during the development of the verte- There are a number of other factors that bind to the TCF- brate and invertebrate central nervous system, sources or gra- catenin complex and are necessary for transcriptional activa- dients of Wnt protein can provide directional guidance to tion, including Legless (Lgs), Pygopus (Pygo), and most recently extending axons by transducing a signal through Ryk, an atyp- discovered hyrax/parafibromin, a member of the polymerase- ical member of the receptor tyrosine kinase (RTK) family associated factor 1 (PAF1) complex (25–28). Lgs and Pygo are (41–43). an intriguing pair of proteins that associate with -catenin in Just as PCP is most likely an example of Wnt-independent Fz the nucleus. Lgs binds directly to the N terminus of -catenin function, the association of Wnt and RTKs may illustrate a Fz- and serves as an adaptor to attach Pygo to the complex (25). independent function for Wnt (Fig. 2). Certain atypical mem- However, the essential function of Pygo is controversial; ini- bers of the RTK family have an extracellular Wnt binding tially thought of as a nuclear cofactor that enhances transcrip- domain, cysteine-rich domains in the case of Ror1 and Ror2 and tional activation by the TCF-catenin complex (25–27), a sub- a WIF (Wnt inhibitory factor) domain in the case of Ryk (44). sequent report suggested that Pygo affects transcription by The Drosophila homolog of Ryk, Derailed, is an axon guidance recruiting otherwise cytoplasmic -catenin to the nucleus (29), receptor that mediates repulsion from Wnt5 during embryonic a claim that has since been refuted in favor of the original model central nervous system patterning, a process that apparently (30). Additionally, the activity of TCF itself may be modulated does not involve Dsh or downstream canonical signaling com- by signaling from the mitogen-activated protein kinase cascade ponents (41). Similarly, a number of Wnts, including Wnt5a (a composed of TAK1 and NLK/Nemo (31), and TCF/LEF-inde- mammalian ortholog of Drosophila Wnt5), have been shown to pendent signaling by -catenin can occur through interactions act through Ryk as axon repellents during mammalian central with other DNA-binding proteins, including Pitx2 and Prop1 nervous system development (42). Whether the fly and mouse (32, 33). The latter case is further complicated by the observa- processes are homologous is not known, and an answer will tion that the Prop1-catenin complex can act both as an acti- require more detailed knowledge of the other protein compo- vator of transcription and also as a repressor, a function medi- nents mediating these signals. Moreover, Wnt5a can block ated by binding to the co-repressor Groucho (33). In all, the canonical signaling in a process that depends on another RTK, AUGUST 11, 2006• VOLUME 281 • NUMBER 32 JOURNAL OF BIOLOGICAL CHEMISTRY 22431 MINIREVIEW: Wnt Signaling Ror2 (45). Clearly, there is much work still to be done in defin- Second, evidence that mis-regulation of Wnt signaling is a con- ing the signal transduction pathways downstream of Wnt- tributing factor in a number of human diseases continues to binding RTKs and sorting out the specificities of each ligand/ accumulate. The most famous example is that of APC, muta- receptor(s) interaction in modulating axon guidance or tion of which causes familial adenomatous polyposis, a condi- -catenin stability. tion that inevitably leads to colorectal cancer (see Ref. 53). However, mutations in Wnts or Wnt signaling components Wnt Family History have been associated with diseases that cover a wide spectrum By reading even a cursory review such as this one, it is easy to of afflictions, from arthritis to schizophrenia (see Ref. 54). appreciate the enormous complexity of Wnt signaling. The Lastly, Wnts appear able to expand, or perhaps maintain, cer- large number and diversity of components utilized in transduc- tain undifferentiated stem cell populations (49). This observa- tion of Wnt signals is staggering and at least partially underlies tion has made Wnts more than just targets for understanding the specificity seen in the way a particular cell responds to a and potentially treating disease; Wnt proteins hold potential as given Wnt. How did Wnt signaling acquire such diversity and agents to manipulate multipotent cells in vitro and could pro- complexity? Part of the answer may come from the recent dis- vide a key element in developing stem cell-derived tissue covery that each Wnt gene has had a surprisingly large amount replacement therapies. of time to evolve independently of the others. Mammals have 19 Even as our understanding of the Wnt pathway continues to Wnt genes that, through phylogenetic analysis, can be placed expand, there are a number of important questions that remain. into 12 subfamilies (46, 47). The surprising observation is that In terms of signal transduction, the details of how signaling is these subfamilies are not the result of any recent evolutionary initiated upon Wnt binding to Fz and LRP need to be addressed diversification; at least 11 of these subfamilies are present in further, as does the mechanism by which the -catenin destruc- Cnidaria (specifically, the sea anemone Nematostella vectensis), tion complex is regulated. More daunting perhaps is the ques- a group that split from the last common ancestor of Bilaterians tion of how specificity is achieved in the nuclear activity of (chordates, flies, worms, etc.) very early in metazoan evolution -catenin and its regulation of target genes: How does cell iden- (48). This indicates that the acquisition of the Wnt subfamilies tity and the integration of other signals influence the set of was an early development in the evolution of metazoa and likely genes transcribed upon Wnt signal activation? Manipulating occurred about 650 million years ago (48). What was the reason this specificity using small molecules that target the proteins for early expansion of the Wnt family and its maintenance along involved could hold promise in treating specific disease pro- multiple disparate lineages over many millions of years? cesses. Additionally, as interest in using Wnt ligands in more The Wnt family’s long evolutionary history raises another therapeutic settings increases, it will be important to under- question: whether, aside from amino acid sequence similarity, stand more thoroughly the biochemical characteristics of these there are any universal properties of Wnts. The recent discov- proteins and the distinguishing characteristics of each family ery that Wnt proteins can be purified to homogeneity allows for member. Finally, it will be interesting to see whether we can some unique opportunities to address this issue and has already integrate the large amount of information we have on canonical raised one possible universal feature (49). Long known to be Wnt signaling with the increasing number of examples of poorly soluble in aqueous solution, it was discovered that Wnts -catenin-independent signaling. 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Journal

Journal of Biological Chemistry – American Society for Biochemistry and Molecular Biology

Published: Aug 11, 2006

References