What Happened to the IGF Binding Proteins?

What Happened to the IGF Binding Proteins? Abstract Insulinlike growth factor (IGF) binding proteins (IGFBPs) 1 to 6 are high-affinity regulators of IGF activity. They generally inhibit IGF actions by preventing binding to the IGF-I receptor but can also enhance their actions under some conditions. Posttranslational modifications such as glycosylation and phosphorylation modulate IGFBP properties, and IGFBP proteolysis results in IGF release. IGFBPs have more recently been shown to have IGF-independent actions. A number of mechanisms are involved, including modulation of other growth factor pathways, nuclear localization and transcriptional regulation, interaction with the sphingolipid pathway, and binding to non-IGF biomolecules in the extracellular space and matrix, on the cell surface and intracellularly. IGFBPs modulate important biological processes, including cell proliferation, survival, migration, senescence, autophagy, and angiogenesis. Their actions have been implicated in growth, metabolism, cancer, stem cell maintenance and differentiation, and immune regulation. Recent studies have shown that epigenetic mechanisms are involved in the regulation of IGFBP abundance. A more complete understanding of IGFBP biology is necessary to further define their cellular roles and determine their therapeutic potential. At the recent ENDO 2017 (Endocrine Society Annual Meeting) meeting in Orlando, Florida, Peter Rotwein and I caught up over dinner and were chatting about many things, including our recent research. Having known each other for many years owing to our common interest in the insulinlike growth factor (IGF) system, we were lamenting the relative paucity of IGF-related presentations at the meeting compared with the late 1990s and early 2000s, when ≤10% of the program content anecdotally related to this system. In particular, Peter asked me, “What happened to the IGF binding proteins (IGFBPs)?”, which stimulated this mini-review. Notwithstanding that a search of the ENDO 2017 program for “IGFBP” revealed only 18 abstracts, an admittedly crude search on the Web of Science website (1) showed that 376 studies were reported on this topic and 16,509 citations received in 2016 compared with peaks of 456 in 2007 and 17,442 in 2015, respectively. The IGFBPs certainly have not gone away, and understanding their actions remains crucial to deciphering the role of the IGF system in normal physiology and disease. In addition, the IGF-independent actions of IGFBPs have been implicated in a range of biological processes. IGF-I and IGF-II are widely expressed peptides with essential physiological roles in growth, development, and metabolism (2). IGF-I mediates many of the effects of growth hormone, and both IGFs share substantial sequence homology with proinsulin and have insulinlike metabolic effects. Consistent with the free hormone hypothesis, which states that the biological activity of a hormone is related to its unbound rather than total concentration (3), IGFBPs were initially seen as circulating carrier proteins that inhibited IGF actions by preventing their egress from the vasculature and subsequent binding to tissue IGF receptors. When the six individual IGFBPs were identified and cloned, it was recognized that their expression is widespread, suggesting that they might be paracrine/autocrine and endocrine regulators of IGF actions (4–6). It was also recognized that some IGFBPs might potentiate IGF actions in some circumstances, suggesting that they were more than passive inhibitors. Finally, IGF-independent actions of individual IGFBPs have been reported, broadening their relevance beyond the IGF system. The present mini-review focuses on our contemporary understanding of the roles of IGFBPs in important biological processes; however, some fundamental common features of this protein family are described first. The six high-affinity IGFBPs share a three-domain structure (Fig. 1) (7). Their N- and C-terminal domains each have a high degree of homology and share a number of conserved disulfide linkages. The N-terminal domain contains a high-affinity IGF-binding domain, and a broad binding surface in the C-terminal domain also contributes to IGF binding. The IGFBPs, therefore, bind IGFs with high affinity but, importantly, do not bind the closely related peptide insulin. The C-terminal domains of some IGFBPs contain a highly basic region that includes heparin binding and nuclear localization motifs, which contribute to both their IGF-dependent and IGF-independent actions. This domain also contains an integrin binding Arg-Gly-Asp motif in IGFBP-1 and IGFBP-2, contributing to their actions. The linker domains of the IGFBPs are not homologous and do not directly contribute to IGF binding. They are thought to be flexible and unstructured and are sites of individual IGFBP-specific posttranslational modifications such as glycosylation and phosphorylation, which modify properties such as cell association, circulating half-life, and IGF binding affinity. The linker domains also contain specific proteolytic recognition sites, and IGFBP cleavage resulting in decreased IGF binding affinity is thought to be a physiological mechanism for release of free IGFs (8). Figure 1. View largeDownload slide Domain structure of IGFBPs. Both the N- and C-terminal domains of IGFBPs 1 to 6 are highly conserved, including a number of disulfide linkages (solid red lines); only the N-terminal disulfides of IGFBP-6 differ from those of the other IGFBPs. High-affinity IGF binding is conferred by regions in both domains (blue boxes). The C-domains of some IGFBPs contain functionally relevant sequences, including a heparin-binding motif and a nuclear localization sequence in IGFBP-3, IGFBP-5, and IGFBP-6 and an integrin-binding RGD sequence in IGFBP-1 and IGFBP-2. The linker domain is a site of posttranslational modifications and has heparin binding and nuclear localization sequences in IGFBP-2. Figure 1. View largeDownload slide Domain structure of IGFBPs. Both the N- and C-terminal domains of IGFBPs 1 to 6 are highly conserved, including a number of disulfide linkages (solid red lines); only the N-terminal disulfides of IGFBP-6 differ from those of the other IGFBPs. High-affinity IGF binding is conferred by regions in both domains (blue boxes). The C-domains of some IGFBPs contain functionally relevant sequences, including a heparin-binding motif and a nuclear localization sequence in IGFBP-3, IGFBP-5, and IGFBP-6 and an integrin-binding RGD sequence in IGFBP-1 and IGFBP-2. The linker domain is a site of posttranslational modifications and has heparin binding and nuclear localization sequences in IGFBP-2. Cancer IGF-I and IGF-II are autocrine factors for many cancers, and activation of the IGF-I receptor, the predominant signaling receptor for IGF actions, is important for cellular transformation in vitro (9, 10). Many studies have shown that IGFBPs decrease tumor growth by inhibiting IGF actions, including cell proliferation, survival, and migration/invasion (11). During the past two decades, IGF-independent actions of IGFBPs, including inhibition of proliferation and promotion of apoptosis, have also been shown to contribute to decreased tumor growth. Although mutations of IGFBPs have not been directly demonstrated, their expression is decreased in many tumors, and it has been postulated that this contributes to their development. In contrast, some studies have also shown protumorigenic actions of individual IGFBPs, including promotion of cell survival and migration/invasion. In particular, IGFBP-2 appears to be predominantly tumorigenic in a range of cancers, including glioma, and its circulating levels have correlated with aggressiveness and other well-described tumor markers in prostate, breast, and ovarian cancer (12). IGF-independent mechanisms for IGFBP actions on cancer cells include (1) binding and activation of specific IGFBP receptors (although these largely remain poorly characterized); (2) modulation of other pathways, including epidermal growth factor, transforming growth factor-β, and vascular endothelial growth factor (VEGF); and (3) direct or indirect transcriptional effects after nuclear entry of IGFBPs (11). For example, binding of IGFBP-2 via its Arg-Gly-Asp motif to the α5β1 and αVβ3 integrins mediates some of its pro- and antitumorigenic IGF-independent actions (12). IGFBP-6 promotes cancer cell migration via a mechanism involving binding to cell surface prohibitin-2 and activation of mitogen-activated protein kinase pathways (13). Interaction of IGFBP-3 with the mitogen-activated transforming growth factor-β pathway underlies some of its effects in breast cancer cells (14). In contrast, it inhibits Wnt signaling in melanoma cells (15). Within the nucleus, IGFBP-3 interacts with a number of nuclear receptors, including retinoic acid receptor-α, peroxisome proliferator–activated receptor-γ, the vitamin D receptor, and Nur77 (nerve growth factor IB), which underlies some of its effects on apoptosis, proliferation, and differentiation (16). Factors determining the antitumorigenic vs protumorigenic actions of IGFBPs require further study; however, modulation of sphingolipids has been identified as a contributing factor for IGFBP-3 (17) and IGFBP-5 (18). Other effects of IGFBPs on biological processes that contribute to tumorigenesis are outlined in the following sections. Angiogenesis Angiogenesis is the formation of new vessels from pre-existing ones. This process is driven by hypoxia and is important during development and in a number of diseases. Impaired angiogenesis could contribute to ischemic damage after myocardial infarction or stroke. In contrast, angiogenesis is essential for the growth of solid tumors beyond a critical size and for diabetic retinopathy. Indeed, angiogenesis inhibitors are in clinical use for these latter diseases. The VEGF system is the major mediator of angiogenesis; however, the IGF system also plays a role, at least in part by inducing VEGF synthesis (19). Each of the IGFBPs modulate angiogenesis, and both IGF-dependent and IGF-independent mechanisms are involved. Macrophage colony-stimulating factor promoted angiogenesis at least in part by inducing IGFBP-1 in microglial cells (20). IGFBP-2 also promoted angiogenesis by transactivating VEGF gene expression (21). In contrast, microRNA (miR)-126 suppressed metastatic endothelial cell recruitment and angiogenesis by decreasing the expression of genes, including IGFBP2, the effect of which is IGF-dependent (22). In contrast, IGFBP-3 inhibited vessel formation in prostate cancer xenografts by an IGF-independent mechanism (23), and it also inhibited IGF-I– and VEGF-induced proliferation and survival of endothelial cells (24). However, IGFBP-3 enhanced angiogenesis in an IGF-dependent manner by a mechanism involving sphingosine kinase activation in vitro (25). IGFBP-4 inhibited angiogenesis induced by IGF-I and fibroblast growth factor-2 but not VEGF ex vivo (26). This action had both IGF-dependent and IGF-independent components, and inhibition of cathepsin B contributed to the latter (27). IGFBP-5 also inhibited VEGF-induced proliferation, invasion, and tube formation of endothelial cells in vitro and inhibited angiogenesis in ovarian cancer xenografts (28). The C-terminal domain of IGFBP-5 and a peptide based on its heparin binding site both inhibited VEGF signaling, angiogenesis, and growth of ovarian cancer xenografts (29). Furthermore, IGFBP-5 inhibited angiogenesis induced by activated coagulation factor Xa in vitro (30). IGFBP-6 also inhibited basal and VEGF-induced angiogenesis by an IGF-independent mechanism in vitro and inhibited this process in rhabdomyosarcoma xenografts and zebrafish embryos in vivo (31). Because its expression is increased by hypoxia, it has been proposed that IGFBP-6 might limit the angiogenic response to this stimulus. Senescence Senescent cells are metabolically active but cell cycle arrested. Senescence is associated with cellular stress and aging; however, it has also been linked to tumor suppression. The IGF system has been implicated in this process. IGFBP-3 promoted senescence associated with aging (32) and in response to cellular stress (33) via mechanisms involving Akt, p53, and Rb. IGFBP-4 levels were increased in senescent mesenchymal stem cells, and it promoted their senescence (34). IGFBP-5 also induced senescence via a p53-dependent pathway (35) and mediated the endothelial cell senescence induced by activated coagulation factor Xa (30). Senescence induced by various stimuli was also associated with increased IGFBP-6 levels (36). Autophagy There has been a great amount of interest in autophagy in recent years. This process, in which intracellular components are degraded by lysosomes, might be a response to stress and is important for cellular homeostasis. Although autophagy might be a protective mechanism in many diseases, including cancer, it might also allow cancer cells to evade apoptosis in some circumstances. IGFBP-3 promoted the survival of breast cancer cells exposed to low glucose and hypoxia, and this was dependent on increased autophagy after binding to GRP78, an endoplasmic reticulum protein (37). IGFBP-3 also activated autophagy in bronchial epithelial cells by a mechanism involving translocation of the transcription factor Nur77 from the nucleus (38). It was also recently shown that IGFBP-2 and IGF-I cooperatively modulated adenosine 5′-monophosphate kinase and autophagy to optimize the early and late stages of osteoblast differentiation (39). Stem Cells The IGF system has been implicated in the maintenance and differentiation of stem cells and lineage precursors, and individual IGFBPs are also involved. IGFBP-2 supported the survival of hematopoietic stem cells via an IGF-independent pathway (40) and also promoted glioma stem cell expansion and survival (41). Wnt signaling inhibited adult cardiac progenitor cell proliferation via IGFBP-3 acting in an IGF-dependent manner (42). In contrast, inhibition of mesenchymal chondroprogenitor proliferation by IGFBP-3 was IGF-independent (43). During oxygen-induced retinopathy, IGFBP-3 expression increased the differentiation of endothelial precursor cells to endothelial cells (44, 45). IGFBP-3, but not other IGFBPs, inhibited IGF-I–induced differentiation of human hematopoietic stem cells into pro-B cells in vitro, whereas IGFBP-6 was required for this process (46). IGFBP-6 also inhibited the survival and proliferation of oligodendrocyte precursor cells (47). IGFBP-4 promoted senescence of mesenchymal stem cells, and this process was implicated in age-related impairment of osteogenic differentiation (34, 48). However, it increased differentiation of induced pluripotent stem cells into cardiomyocytes by inhibiting β-catenin signaling (49). Furthermore, IGFBP-4 secreted by human mesenchymal stem cells inhibited IGF-stimulated induction of regulatory T lymphocytes (50). Epigenetics Epigenetic mechanisms of gene regulation include methylation of DNA resulting in inhibition of expression, histone protein modifications that regulate transcription by chromatin remodeling, and noncoding microRNAs (miRNAs) that suppress translation. Each of these mechanisms has been reported for individual IGFBPs. Although IGFBP mutations have not been identified in disease states, epigenetic suppression of IGFBP expression could contribute to tumorigenesis by increasing IGF activity and decreasing antitumorigenic IGF-independent actions. Epigenetic regulation might also contribute to the pathogenesis of other diseases as described in the following sections. Identification of IGFBP promoter methylation and/or regulation by miRNA might additionally lead to the development of disease biomarkers or prognostic indicators (51). DNA methylation Hypermethylation of the IGFBP3 promoter has been reported in a range of cancers, resulting in decreased expression. Furthermore, methylation might be a marker of a more aggressive phenotype (52). Similarly, hypermethylation of the IGFBP4 promoter was found in 42% of lung adenocarcinomas (53), and the IGFBP6 promoter was hypermethylated in 23% of gastric cancers (54). Epigenetic regulation of IGFBPs by DNA methylation has also been implicated in diseases other than cancer. Hypermethylation of IGFBP3 by amyloid-β resulted in neural cell apoptosis, suggesting a possible role in Alzheimer disease (55). Decreased placental methylation and increased expression of IGFBP1-4 promoters might contribute to fetal growth disorders (56). In a mouse model, IGFBP2 promoter hypermethylation early in life was associated with impaired glucose homeostasis, and it preceded obesity and liver fat accumulation later in life (57). The IGFBP6 promoter was hypermethylated and messenger RNA (mRNA) levels were decreased in peripheral blood mononuclear cells from HIV-infected subjects, although the functional significance of this observation is unknown (58). Histone modification Hyperglycemia increased chemoresistance of prostate cancer cells by increasing IGFBP2 expression via enhanced histone acetylation (59). IGFBP1 expression was increased in decidualizing endometrial stromal cells, an effect mediated by C/EBPβ-induced histone acetylation (60). IGFBP5 expression was increased by histone demethylation in periodontal mesenchymal stem cells (61). In addition to promoter methylation, IGFBP3 levels in cancer cells were also regulated by histone acetylation (52). miRNA miRNAs are small noncoding RNAs that have an important role in gene regulation. They bind to the 3′ untranslated region of target mRNAs, promoting their cleavage and suppressing translation. Each miRNA binds to multiple mRNA targets; thus, they can modulate a biological “program,” and they have been implicated in many diseases. miRNA regulation has been described for IGFBPs 1 to 5. For example, miR-200s suppressed Sec23a, a protein secretory pathway regulator, resulting in decreased IGFBP-4 secretion, which might play a role in metastatic colonization (62). miR-126 is silenced in a number of common human cancers, and it targets IGFBP-2, which is secreted by cancer cells, and stimulates IGF-dependent endothelial recruitment and angiogenesis (22). miR-143/5 downregulation has been implicated in colon cancer, and it has a role in epithelial regeneration after injury. IGFBP5, which modulates IGF responsiveness in this system, is a target (63). miR-21 downregulated IGFBP3, thereby contributing to glioblastoma tumorigenesis (64). Downregulation of miR-542-3p in decidualizing endometrial stromal cells increased expression of IGFBP-1, which has autocrine and/or paracrine roles in this process (65). Although miRNA regulation of IGFBP6 has not been reported, its expression was decreased by Uc.416+A, one of a novel class of noncoding transcribed-ultraconserved regions RNAs, and it was suggested that this might promote gastric cancer cell proliferation (66). Metabolism IGFs have direct insulinlike metabolic effects, and IGF injection decreases plasma glucose with ∼7% of the potency of insulin. Because IGFs circulate in ∼1000-fold greater concentrations than insulin, circulating IGFBPs (predominantly IGFBP-3 in a ternary complex with the acid-labile subunit) prevent profound hypoglycemia. Secretion by tumors of a partially processed form of IGF-II that is unable to form these ternary complexes leads to the rare syndrome of non–islet cell tumor hypoglycemia (67). IGFBP-1 and IGFBP-2 are regulated metabolically and might make specific physiological contributions (68). IGFBP-1 levels are rapidly regulated by insulin, which inhibits its transcription (69). Levels are therefore greater in the fasting state and decreased after eating. They are also greater in subjects with type 1 diabetes and are high relative to the insulin levels in insulin-resistant subjects with type 2 diabetes. Low-fasting IGFBP-1 levels predicted the development of dysglycemia and type 2 diabetes (70). Consistent with this, transgenic mice with IGFBP-1 overexpression under the native promoter were protected from obesity-induced insulin resistance and glucose intolerance (68). Recent studies have suggested intriguing novel mechanisms whereby IGFBP-1 might be protective from diabetes. One of these showed that IGFBP-1 might increase regeneration of pancreatic β-cells by promoting transdifferentiation of glucagon-producing α-cells (71). Another showed that IGFBP-1 enhanced insulin sensitivity in an IGF-independent manner via its Arg-Gly-Asp sequence and that a peptide based on this sequence also enhanced insulin sensitivity in vivo (72). However, an IGFBP-1 blocking antibody had no effect on the fibroblast growth factor-21–induced increase in insulin sensitivity in vivo (73). IGFBP-2 levels are also metabolically regulated but more slowly than IGFBP-1 (12, 68). IGFBP-2 is insulin responsive, and levels are high in those with type 1 diabetes but low in those with type 2 diabetes. IGFBP-2 might have a role in weight regulation, because it is expressed in adipose tissue and its expression is regulated by leptin (74). Its levels decreased with increasing adiposity (12). IGFBP-2 overexpression under the control of its native promoter in mice resulted in protection from diet-induced obesity and insulin resistance (75). Immune Regulation The IGF system plays a role in immune regulation and has been implicated in some autoimmune diseases (76). IGFBPs are synthesized by lymphoid and myeloid cells and by cells that regulate proliferation and differentiation of these lineages. Mesenchymal stem cells inhibited proliferation of peripheral blood mononuclear cells in vitro, and this effect was partly due to IGFBP-2 and IGFBP-3 (77). As stated previously, IGFBP-4 secreted by human mesenchymal stem cells inhibited IGF-stimulated induction of regulatory T lymphocytes (50). IGFBP-6 was required for pro–B-cell development in vitro, whereas IGFBP-3 inhibited this process (46). IGFBP-6 and IGFBP-1 expression were increased by proinflammatory cytokines after infection in fish, and this might divert energy toward immune system activation by suppressing IGF-mediated growth (78). IGFBPs might also be chemotactic agents for leukocytes. IGFBP-3 enhanced breast cancer growth in immunocompetent mice and suppressed tumor infiltration by T lymphocytes but not macrophages (79). In dendritic cells, hyperthermia increased expression of IGFBP-6, which promoted monocyte and T-lymphocyte chemotaxis; therefore, IGFBP-6 might play a role in the adaptive immune response (80). IGFBP-6 also promoted chemotaxis of T lymphocytes from subjects with rheumatoid arthritis but not those with osteoarthritis or healthy controls, suggesting that it might also have a pathogenic role in this autoimmune disease (81). Growth No IGFBP mutations have been associated with human growth phenotypes (82). However, a number of families with mutations in the acid labile subunit gene (IGFALS) have been described (83). The acid labile subunit forms a ternary complex with IGFBP-3 or IGFBP-5 and IGFs, which prolongs the circulating half-life of the latter. Patients with absent acid labile subunit due to gene mutations had severely decreased IGF-I and IGFBP-3 levels, with variable and mild growth impairment and insulin resistance. The disproportionately mild growth deficit might result from unaltered autocrine and paracrine IGF action in these patients. IGFBPs are cleaved by a range of proteases, including the pregnancy-associated plasma protein A (PAPP-A) family (84). Children from two families with loss-of-function PAPPA2 mutations had short stature despite high circulating IGF-I and IGF-II levels and high levels of the PAPP-A2 substrates IGFBP-3 and IGFBP-5. The growth deficit was attributed to impaired IGFBP proteolysis, leading to IGF retention within IGFBP-containing complexes and low free IGF levels. In support of a role for IGFBP proteolysis in human growth, increased human adult height was associated with two coding variants of the STC2 gene, which encodes stanniocalcin-2, a PAPP-A inhibitor (85). These variants had decreased PAPP-A inhibitory activity in vitro, resulting in increased IGFBP-4 cleavage and presumably enhanced IGF bioactivity. Conclusion This brief survey has summarized the broad range of biological processes in which the protean IGFBP family is involved. However, many outstanding questions regarding the IGFBPs remain: Although their role in regulating IGF actions is clear, what are the determinants and relative balance of their IGF-dependent and IGF-independent actions? What is the physiological significance of the binding of different IGFBPs to a range of non-IGF ligands? What are the specific IGFBP receptors and signaling pathways involved in IGF-independent actions? What are the mechanisms underlying intracellular and nuclear localization of IGFBPs and their subsequent actions? What is the balance of IGF-dependent and IGF-independent actions of IGFBPs in vivo, including in disease states? Finally, what is the therapeutic potential of IGFBPs either as IGF inhibitors or via their IGF-independent actions? To answer this question, a fuller understanding of their properties, as outlined in questions 1 through 5, is required. For example, the antiproliferative, proapoptotic, and antiangiogenic actions of IGFBPs are desirable properties of a cancer therapeutic agent. However, other properties such as the promotion of migration might contribute to tumorigenic behavior, and IGFBP-2, in particular, appears to be protumorigenic. It is, therefore, necessary to delineate the determinants of these effects. Apart from direct IGFBP-based therapies, other approaches such as epigenetic reprogramming leading to derepression of genes, including IGFBPs, in diseases such as cancer are also in development. Because one of the initial lines of inquiry leading to the discovery of the IGF system was its relationship to metabolism, the IGFs became the domain of the endocrine community and the US Endocrine Society meeting was the de facto international IGF meeting for many years. With our increasing understanding that this system, including the IGFBPs, is involved so widely in other disease processes, researchers from other fields became involved. This might explain in part why the IGF representation at endocrine meetings has waned in recent years. To paraphrase a quote attributed to Mark Twain, “the report of their death has been grossly exaggerated.” Abbreviations: IGF insulinlike growth factor IGFBP insulinlike growth factor binding protein miR miRNA, microRNA mRNA messenger RNA PAPP-A pregnancy-associated plasma protein A VEGF vascular endothelial growth factor. Acknowledgments Disclosure Summary: The author has nothing to disclose. References 1. Web of Science. 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Rare and low-frequency coding variants alter human adult height. Nature . 2017; 542( 7640): 186– 190. Google Scholar CrossRef Search ADS PubMed  Copyright © 2018 Endocrine Society http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Endocrinology Oxford University Press

What Happened to the IGF Binding Proteins?

Endocrinology , Volume 159 (2) – Feb 1, 2018

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Endocrine Society
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Copyright © 2018 Endocrine Society
ISSN
0013-7227
eISSN
1945-7170
D.O.I.
10.1210/en.2017-00908
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Abstract

Abstract Insulinlike growth factor (IGF) binding proteins (IGFBPs) 1 to 6 are high-affinity regulators of IGF activity. They generally inhibit IGF actions by preventing binding to the IGF-I receptor but can also enhance their actions under some conditions. Posttranslational modifications such as glycosylation and phosphorylation modulate IGFBP properties, and IGFBP proteolysis results in IGF release. IGFBPs have more recently been shown to have IGF-independent actions. A number of mechanisms are involved, including modulation of other growth factor pathways, nuclear localization and transcriptional regulation, interaction with the sphingolipid pathway, and binding to non-IGF biomolecules in the extracellular space and matrix, on the cell surface and intracellularly. IGFBPs modulate important biological processes, including cell proliferation, survival, migration, senescence, autophagy, and angiogenesis. Their actions have been implicated in growth, metabolism, cancer, stem cell maintenance and differentiation, and immune regulation. Recent studies have shown that epigenetic mechanisms are involved in the regulation of IGFBP abundance. A more complete understanding of IGFBP biology is necessary to further define their cellular roles and determine their therapeutic potential. At the recent ENDO 2017 (Endocrine Society Annual Meeting) meeting in Orlando, Florida, Peter Rotwein and I caught up over dinner and were chatting about many things, including our recent research. Having known each other for many years owing to our common interest in the insulinlike growth factor (IGF) system, we were lamenting the relative paucity of IGF-related presentations at the meeting compared with the late 1990s and early 2000s, when ≤10% of the program content anecdotally related to this system. In particular, Peter asked me, “What happened to the IGF binding proteins (IGFBPs)?”, which stimulated this mini-review. Notwithstanding that a search of the ENDO 2017 program for “IGFBP” revealed only 18 abstracts, an admittedly crude search on the Web of Science website (1) showed that 376 studies were reported on this topic and 16,509 citations received in 2016 compared with peaks of 456 in 2007 and 17,442 in 2015, respectively. The IGFBPs certainly have not gone away, and understanding their actions remains crucial to deciphering the role of the IGF system in normal physiology and disease. In addition, the IGF-independent actions of IGFBPs have been implicated in a range of biological processes. IGF-I and IGF-II are widely expressed peptides with essential physiological roles in growth, development, and metabolism (2). IGF-I mediates many of the effects of growth hormone, and both IGFs share substantial sequence homology with proinsulin and have insulinlike metabolic effects. Consistent with the free hormone hypothesis, which states that the biological activity of a hormone is related to its unbound rather than total concentration (3), IGFBPs were initially seen as circulating carrier proteins that inhibited IGF actions by preventing their egress from the vasculature and subsequent binding to tissue IGF receptors. When the six individual IGFBPs were identified and cloned, it was recognized that their expression is widespread, suggesting that they might be paracrine/autocrine and endocrine regulators of IGF actions (4–6). It was also recognized that some IGFBPs might potentiate IGF actions in some circumstances, suggesting that they were more than passive inhibitors. Finally, IGF-independent actions of individual IGFBPs have been reported, broadening their relevance beyond the IGF system. The present mini-review focuses on our contemporary understanding of the roles of IGFBPs in important biological processes; however, some fundamental common features of this protein family are described first. The six high-affinity IGFBPs share a three-domain structure (Fig. 1) (7). Their N- and C-terminal domains each have a high degree of homology and share a number of conserved disulfide linkages. The N-terminal domain contains a high-affinity IGF-binding domain, and a broad binding surface in the C-terminal domain also contributes to IGF binding. The IGFBPs, therefore, bind IGFs with high affinity but, importantly, do not bind the closely related peptide insulin. The C-terminal domains of some IGFBPs contain a highly basic region that includes heparin binding and nuclear localization motifs, which contribute to both their IGF-dependent and IGF-independent actions. This domain also contains an integrin binding Arg-Gly-Asp motif in IGFBP-1 and IGFBP-2, contributing to their actions. The linker domains of the IGFBPs are not homologous and do not directly contribute to IGF binding. They are thought to be flexible and unstructured and are sites of individual IGFBP-specific posttranslational modifications such as glycosylation and phosphorylation, which modify properties such as cell association, circulating half-life, and IGF binding affinity. The linker domains also contain specific proteolytic recognition sites, and IGFBP cleavage resulting in decreased IGF binding affinity is thought to be a physiological mechanism for release of free IGFs (8). Figure 1. View largeDownload slide Domain structure of IGFBPs. Both the N- and C-terminal domains of IGFBPs 1 to 6 are highly conserved, including a number of disulfide linkages (solid red lines); only the N-terminal disulfides of IGFBP-6 differ from those of the other IGFBPs. High-affinity IGF binding is conferred by regions in both domains (blue boxes). The C-domains of some IGFBPs contain functionally relevant sequences, including a heparin-binding motif and a nuclear localization sequence in IGFBP-3, IGFBP-5, and IGFBP-6 and an integrin-binding RGD sequence in IGFBP-1 and IGFBP-2. The linker domain is a site of posttranslational modifications and has heparin binding and nuclear localization sequences in IGFBP-2. Figure 1. View largeDownload slide Domain structure of IGFBPs. Both the N- and C-terminal domains of IGFBPs 1 to 6 are highly conserved, including a number of disulfide linkages (solid red lines); only the N-terminal disulfides of IGFBP-6 differ from those of the other IGFBPs. High-affinity IGF binding is conferred by regions in both domains (blue boxes). The C-domains of some IGFBPs contain functionally relevant sequences, including a heparin-binding motif and a nuclear localization sequence in IGFBP-3, IGFBP-5, and IGFBP-6 and an integrin-binding RGD sequence in IGFBP-1 and IGFBP-2. The linker domain is a site of posttranslational modifications and has heparin binding and nuclear localization sequences in IGFBP-2. Cancer IGF-I and IGF-II are autocrine factors for many cancers, and activation of the IGF-I receptor, the predominant signaling receptor for IGF actions, is important for cellular transformation in vitro (9, 10). Many studies have shown that IGFBPs decrease tumor growth by inhibiting IGF actions, including cell proliferation, survival, and migration/invasion (11). During the past two decades, IGF-independent actions of IGFBPs, including inhibition of proliferation and promotion of apoptosis, have also been shown to contribute to decreased tumor growth. Although mutations of IGFBPs have not been directly demonstrated, their expression is decreased in many tumors, and it has been postulated that this contributes to their development. In contrast, some studies have also shown protumorigenic actions of individual IGFBPs, including promotion of cell survival and migration/invasion. In particular, IGFBP-2 appears to be predominantly tumorigenic in a range of cancers, including glioma, and its circulating levels have correlated with aggressiveness and other well-described tumor markers in prostate, breast, and ovarian cancer (12). IGF-independent mechanisms for IGFBP actions on cancer cells include (1) binding and activation of specific IGFBP receptors (although these largely remain poorly characterized); (2) modulation of other pathways, including epidermal growth factor, transforming growth factor-β, and vascular endothelial growth factor (VEGF); and (3) direct or indirect transcriptional effects after nuclear entry of IGFBPs (11). For example, binding of IGFBP-2 via its Arg-Gly-Asp motif to the α5β1 and αVβ3 integrins mediates some of its pro- and antitumorigenic IGF-independent actions (12). IGFBP-6 promotes cancer cell migration via a mechanism involving binding to cell surface prohibitin-2 and activation of mitogen-activated protein kinase pathways (13). Interaction of IGFBP-3 with the mitogen-activated transforming growth factor-β pathway underlies some of its effects in breast cancer cells (14). In contrast, it inhibits Wnt signaling in melanoma cells (15). Within the nucleus, IGFBP-3 interacts with a number of nuclear receptors, including retinoic acid receptor-α, peroxisome proliferator–activated receptor-γ, the vitamin D receptor, and Nur77 (nerve growth factor IB), which underlies some of its effects on apoptosis, proliferation, and differentiation (16). Factors determining the antitumorigenic vs protumorigenic actions of IGFBPs require further study; however, modulation of sphingolipids has been identified as a contributing factor for IGFBP-3 (17) and IGFBP-5 (18). Other effects of IGFBPs on biological processes that contribute to tumorigenesis are outlined in the following sections. Angiogenesis Angiogenesis is the formation of new vessels from pre-existing ones. This process is driven by hypoxia and is important during development and in a number of diseases. Impaired angiogenesis could contribute to ischemic damage after myocardial infarction or stroke. In contrast, angiogenesis is essential for the growth of solid tumors beyond a critical size and for diabetic retinopathy. Indeed, angiogenesis inhibitors are in clinical use for these latter diseases. The VEGF system is the major mediator of angiogenesis; however, the IGF system also plays a role, at least in part by inducing VEGF synthesis (19). Each of the IGFBPs modulate angiogenesis, and both IGF-dependent and IGF-independent mechanisms are involved. Macrophage colony-stimulating factor promoted angiogenesis at least in part by inducing IGFBP-1 in microglial cells (20). IGFBP-2 also promoted angiogenesis by transactivating VEGF gene expression (21). In contrast, microRNA (miR)-126 suppressed metastatic endothelial cell recruitment and angiogenesis by decreasing the expression of genes, including IGFBP2, the effect of which is IGF-dependent (22). In contrast, IGFBP-3 inhibited vessel formation in prostate cancer xenografts by an IGF-independent mechanism (23), and it also inhibited IGF-I– and VEGF-induced proliferation and survival of endothelial cells (24). However, IGFBP-3 enhanced angiogenesis in an IGF-dependent manner by a mechanism involving sphingosine kinase activation in vitro (25). IGFBP-4 inhibited angiogenesis induced by IGF-I and fibroblast growth factor-2 but not VEGF ex vivo (26). This action had both IGF-dependent and IGF-independent components, and inhibition of cathepsin B contributed to the latter (27). IGFBP-5 also inhibited VEGF-induced proliferation, invasion, and tube formation of endothelial cells in vitro and inhibited angiogenesis in ovarian cancer xenografts (28). The C-terminal domain of IGFBP-5 and a peptide based on its heparin binding site both inhibited VEGF signaling, angiogenesis, and growth of ovarian cancer xenografts (29). Furthermore, IGFBP-5 inhibited angiogenesis induced by activated coagulation factor Xa in vitro (30). IGFBP-6 also inhibited basal and VEGF-induced angiogenesis by an IGF-independent mechanism in vitro and inhibited this process in rhabdomyosarcoma xenografts and zebrafish embryos in vivo (31). Because its expression is increased by hypoxia, it has been proposed that IGFBP-6 might limit the angiogenic response to this stimulus. Senescence Senescent cells are metabolically active but cell cycle arrested. Senescence is associated with cellular stress and aging; however, it has also been linked to tumor suppression. The IGF system has been implicated in this process. IGFBP-3 promoted senescence associated with aging (32) and in response to cellular stress (33) via mechanisms involving Akt, p53, and Rb. IGFBP-4 levels were increased in senescent mesenchymal stem cells, and it promoted their senescence (34). IGFBP-5 also induced senescence via a p53-dependent pathway (35) and mediated the endothelial cell senescence induced by activated coagulation factor Xa (30). Senescence induced by various stimuli was also associated with increased IGFBP-6 levels (36). Autophagy There has been a great amount of interest in autophagy in recent years. This process, in which intracellular components are degraded by lysosomes, might be a response to stress and is important for cellular homeostasis. Although autophagy might be a protective mechanism in many diseases, including cancer, it might also allow cancer cells to evade apoptosis in some circumstances. IGFBP-3 promoted the survival of breast cancer cells exposed to low glucose and hypoxia, and this was dependent on increased autophagy after binding to GRP78, an endoplasmic reticulum protein (37). IGFBP-3 also activated autophagy in bronchial epithelial cells by a mechanism involving translocation of the transcription factor Nur77 from the nucleus (38). It was also recently shown that IGFBP-2 and IGF-I cooperatively modulated adenosine 5′-monophosphate kinase and autophagy to optimize the early and late stages of osteoblast differentiation (39). Stem Cells The IGF system has been implicated in the maintenance and differentiation of stem cells and lineage precursors, and individual IGFBPs are also involved. IGFBP-2 supported the survival of hematopoietic stem cells via an IGF-independent pathway (40) and also promoted glioma stem cell expansion and survival (41). Wnt signaling inhibited adult cardiac progenitor cell proliferation via IGFBP-3 acting in an IGF-dependent manner (42). In contrast, inhibition of mesenchymal chondroprogenitor proliferation by IGFBP-3 was IGF-independent (43). During oxygen-induced retinopathy, IGFBP-3 expression increased the differentiation of endothelial precursor cells to endothelial cells (44, 45). IGFBP-3, but not other IGFBPs, inhibited IGF-I–induced differentiation of human hematopoietic stem cells into pro-B cells in vitro, whereas IGFBP-6 was required for this process (46). IGFBP-6 also inhibited the survival and proliferation of oligodendrocyte precursor cells (47). IGFBP-4 promoted senescence of mesenchymal stem cells, and this process was implicated in age-related impairment of osteogenic differentiation (34, 48). However, it increased differentiation of induced pluripotent stem cells into cardiomyocytes by inhibiting β-catenin signaling (49). Furthermore, IGFBP-4 secreted by human mesenchymal stem cells inhibited IGF-stimulated induction of regulatory T lymphocytes (50). Epigenetics Epigenetic mechanisms of gene regulation include methylation of DNA resulting in inhibition of expression, histone protein modifications that regulate transcription by chromatin remodeling, and noncoding microRNAs (miRNAs) that suppress translation. Each of these mechanisms has been reported for individual IGFBPs. Although IGFBP mutations have not been identified in disease states, epigenetic suppression of IGFBP expression could contribute to tumorigenesis by increasing IGF activity and decreasing antitumorigenic IGF-independent actions. Epigenetic regulation might also contribute to the pathogenesis of other diseases as described in the following sections. Identification of IGFBP promoter methylation and/or regulation by miRNA might additionally lead to the development of disease biomarkers or prognostic indicators (51). DNA methylation Hypermethylation of the IGFBP3 promoter has been reported in a range of cancers, resulting in decreased expression. Furthermore, methylation might be a marker of a more aggressive phenotype (52). Similarly, hypermethylation of the IGFBP4 promoter was found in 42% of lung adenocarcinomas (53), and the IGFBP6 promoter was hypermethylated in 23% of gastric cancers (54). Epigenetic regulation of IGFBPs by DNA methylation has also been implicated in diseases other than cancer. Hypermethylation of IGFBP3 by amyloid-β resulted in neural cell apoptosis, suggesting a possible role in Alzheimer disease (55). Decreased placental methylation and increased expression of IGFBP1-4 promoters might contribute to fetal growth disorders (56). In a mouse model, IGFBP2 promoter hypermethylation early in life was associated with impaired glucose homeostasis, and it preceded obesity and liver fat accumulation later in life (57). The IGFBP6 promoter was hypermethylated and messenger RNA (mRNA) levels were decreased in peripheral blood mononuclear cells from HIV-infected subjects, although the functional significance of this observation is unknown (58). Histone modification Hyperglycemia increased chemoresistance of prostate cancer cells by increasing IGFBP2 expression via enhanced histone acetylation (59). IGFBP1 expression was increased in decidualizing endometrial stromal cells, an effect mediated by C/EBPβ-induced histone acetylation (60). IGFBP5 expression was increased by histone demethylation in periodontal mesenchymal stem cells (61). In addition to promoter methylation, IGFBP3 levels in cancer cells were also regulated by histone acetylation (52). miRNA miRNAs are small noncoding RNAs that have an important role in gene regulation. They bind to the 3′ untranslated region of target mRNAs, promoting their cleavage and suppressing translation. Each miRNA binds to multiple mRNA targets; thus, they can modulate a biological “program,” and they have been implicated in many diseases. miRNA regulation has been described for IGFBPs 1 to 5. For example, miR-200s suppressed Sec23a, a protein secretory pathway regulator, resulting in decreased IGFBP-4 secretion, which might play a role in metastatic colonization (62). miR-126 is silenced in a number of common human cancers, and it targets IGFBP-2, which is secreted by cancer cells, and stimulates IGF-dependent endothelial recruitment and angiogenesis (22). miR-143/5 downregulation has been implicated in colon cancer, and it has a role in epithelial regeneration after injury. IGFBP5, which modulates IGF responsiveness in this system, is a target (63). miR-21 downregulated IGFBP3, thereby contributing to glioblastoma tumorigenesis (64). Downregulation of miR-542-3p in decidualizing endometrial stromal cells increased expression of IGFBP-1, which has autocrine and/or paracrine roles in this process (65). Although miRNA regulation of IGFBP6 has not been reported, its expression was decreased by Uc.416+A, one of a novel class of noncoding transcribed-ultraconserved regions RNAs, and it was suggested that this might promote gastric cancer cell proliferation (66). Metabolism IGFs have direct insulinlike metabolic effects, and IGF injection decreases plasma glucose with ∼7% of the potency of insulin. Because IGFs circulate in ∼1000-fold greater concentrations than insulin, circulating IGFBPs (predominantly IGFBP-3 in a ternary complex with the acid-labile subunit) prevent profound hypoglycemia. Secretion by tumors of a partially processed form of IGF-II that is unable to form these ternary complexes leads to the rare syndrome of non–islet cell tumor hypoglycemia (67). IGFBP-1 and IGFBP-2 are regulated metabolically and might make specific physiological contributions (68). IGFBP-1 levels are rapidly regulated by insulin, which inhibits its transcription (69). Levels are therefore greater in the fasting state and decreased after eating. They are also greater in subjects with type 1 diabetes and are high relative to the insulin levels in insulin-resistant subjects with type 2 diabetes. Low-fasting IGFBP-1 levels predicted the development of dysglycemia and type 2 diabetes (70). Consistent with this, transgenic mice with IGFBP-1 overexpression under the native promoter were protected from obesity-induced insulin resistance and glucose intolerance (68). Recent studies have suggested intriguing novel mechanisms whereby IGFBP-1 might be protective from diabetes. One of these showed that IGFBP-1 might increase regeneration of pancreatic β-cells by promoting transdifferentiation of glucagon-producing α-cells (71). Another showed that IGFBP-1 enhanced insulin sensitivity in an IGF-independent manner via its Arg-Gly-Asp sequence and that a peptide based on this sequence also enhanced insulin sensitivity in vivo (72). However, an IGFBP-1 blocking antibody had no effect on the fibroblast growth factor-21–induced increase in insulin sensitivity in vivo (73). IGFBP-2 levels are also metabolically regulated but more slowly than IGFBP-1 (12, 68). IGFBP-2 is insulin responsive, and levels are high in those with type 1 diabetes but low in those with type 2 diabetes. IGFBP-2 might have a role in weight regulation, because it is expressed in adipose tissue and its expression is regulated by leptin (74). Its levels decreased with increasing adiposity (12). IGFBP-2 overexpression under the control of its native promoter in mice resulted in protection from diet-induced obesity and insulin resistance (75). Immune Regulation The IGF system plays a role in immune regulation and has been implicated in some autoimmune diseases (76). IGFBPs are synthesized by lymphoid and myeloid cells and by cells that regulate proliferation and differentiation of these lineages. Mesenchymal stem cells inhibited proliferation of peripheral blood mononuclear cells in vitro, and this effect was partly due to IGFBP-2 and IGFBP-3 (77). As stated previously, IGFBP-4 secreted by human mesenchymal stem cells inhibited IGF-stimulated induction of regulatory T lymphocytes (50). IGFBP-6 was required for pro–B-cell development in vitro, whereas IGFBP-3 inhibited this process (46). IGFBP-6 and IGFBP-1 expression were increased by proinflammatory cytokines after infection in fish, and this might divert energy toward immune system activation by suppressing IGF-mediated growth (78). IGFBPs might also be chemotactic agents for leukocytes. IGFBP-3 enhanced breast cancer growth in immunocompetent mice and suppressed tumor infiltration by T lymphocytes but not macrophages (79). In dendritic cells, hyperthermia increased expression of IGFBP-6, which promoted monocyte and T-lymphocyte chemotaxis; therefore, IGFBP-6 might play a role in the adaptive immune response (80). IGFBP-6 also promoted chemotaxis of T lymphocytes from subjects with rheumatoid arthritis but not those with osteoarthritis or healthy controls, suggesting that it might also have a pathogenic role in this autoimmune disease (81). Growth No IGFBP mutations have been associated with human growth phenotypes (82). However, a number of families with mutations in the acid labile subunit gene (IGFALS) have been described (83). The acid labile subunit forms a ternary complex with IGFBP-3 or IGFBP-5 and IGFs, which prolongs the circulating half-life of the latter. Patients with absent acid labile subunit due to gene mutations had severely decreased IGF-I and IGFBP-3 levels, with variable and mild growth impairment and insulin resistance. The disproportionately mild growth deficit might result from unaltered autocrine and paracrine IGF action in these patients. IGFBPs are cleaved by a range of proteases, including the pregnancy-associated plasma protein A (PAPP-A) family (84). Children from two families with loss-of-function PAPPA2 mutations had short stature despite high circulating IGF-I and IGF-II levels and high levels of the PAPP-A2 substrates IGFBP-3 and IGFBP-5. The growth deficit was attributed to impaired IGFBP proteolysis, leading to IGF retention within IGFBP-containing complexes and low free IGF levels. In support of a role for IGFBP proteolysis in human growth, increased human adult height was associated with two coding variants of the STC2 gene, which encodes stanniocalcin-2, a PAPP-A inhibitor (85). These variants had decreased PAPP-A inhibitory activity in vitro, resulting in increased IGFBP-4 cleavage and presumably enhanced IGF bioactivity. Conclusion This brief survey has summarized the broad range of biological processes in which the protean IGFBP family is involved. However, many outstanding questions regarding the IGFBPs remain: Although their role in regulating IGF actions is clear, what are the determinants and relative balance of their IGF-dependent and IGF-independent actions? What is the physiological significance of the binding of different IGFBPs to a range of non-IGF ligands? What are the specific IGFBP receptors and signaling pathways involved in IGF-independent actions? What are the mechanisms underlying intracellular and nuclear localization of IGFBPs and their subsequent actions? What is the balance of IGF-dependent and IGF-independent actions of IGFBPs in vivo, including in disease states? Finally, what is the therapeutic potential of IGFBPs either as IGF inhibitors or via their IGF-independent actions? To answer this question, a fuller understanding of their properties, as outlined in questions 1 through 5, is required. For example, the antiproliferative, proapoptotic, and antiangiogenic actions of IGFBPs are desirable properties of a cancer therapeutic agent. However, other properties such as the promotion of migration might contribute to tumorigenic behavior, and IGFBP-2, in particular, appears to be protumorigenic. It is, therefore, necessary to delineate the determinants of these effects. Apart from direct IGFBP-based therapies, other approaches such as epigenetic reprogramming leading to derepression of genes, including IGFBPs, in diseases such as cancer are also in development. Because one of the initial lines of inquiry leading to the discovery of the IGF system was its relationship to metabolism, the IGFs became the domain of the endocrine community and the US Endocrine Society meeting was the de facto international IGF meeting for many years. With our increasing understanding that this system, including the IGFBPs, is involved so widely in other disease processes, researchers from other fields became involved. This might explain in part why the IGF representation at endocrine meetings has waned in recent years. To paraphrase a quote attributed to Mark Twain, “the report of their death has been grossly exaggerated.” Abbreviations: IGF insulinlike growth factor IGFBP insulinlike growth factor binding protein miR miRNA, microRNA mRNA messenger RNA PAPP-A pregnancy-associated plasma protein A VEGF vascular endothelial growth factor. Acknowledgments Disclosure Summary: The author has nothing to disclose. References 1. Web of Science. 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