Signaling Pathways of the Insulin-like Growth Factor Binding Proteins

Abstract

The 6 high-affinity insulin-like growth factor binding proteins (IGFBPs) are multifunctional proteins that modulate cell signaling through multiple pathways. Their canonical function at the cellular level is to impede access of insulin-like growth factor (IGF)-1 and IGF-2 to their principal receptor IGF1R, but IGFBPs can also inhibit, or sometimes enhance, IGF1R signaling either through their own post-translational modifications, such as phosphorylation or limited proteolysis, or by their interactions with other regulatory proteins. Beyond the regulation of IGF1R activity, IGFBPs have been shown to modulate cell survival, migration, metabolism, and other functions through mechanisms that do not appear to involve the IGF-IGF1R system. This is achieved by interacting directly or functionally with integrins, transforming growth factor β family receptors, and other cell-surface proteins as well as intracellular ligands that are intermediates in a wide range of pathways. Within the nucleus, IGFBPs can regulate the diverse range of functions of class II nuclear hormone receptors and have roles in both cell senescence and DNA damage repair by the nonhomologous end-joining pathway, thus potentially modifying the efficacy of certain cancer therapeutics. They also modulate some immune functions and may have a role in autoimmune conditions such as rheumatoid arthritis. IGFBPs have been proposed as attractive therapeutic targets, but their ubiquity in the circulation and at the cellular level raises many challenges. By understanding the diversity of regulatory pathways with which IGFBPs interact, there may still be therapeutic opportunities based on modulation of IGFBP-dependent signaling.

Keywords: IGF; IGF binding protein; cell-surface; nucleus; receptor; signaling.

Graphical Abstract

Figure 1.

IGFBP inhibition of IGF1R signaling. Hyperphosphorylation of key serine residues of IGFBP-1 increases its affinity for IGFs, thus preventing IGF activation of IGF1R (also see Fig. 2) (48). High-affinity IGF binding by IGFBP-4, which blocks IGF action, is greatly decreased by limited proteolysis by the secreted metalloproteinase PAPP-A, which releases bound IGFs. The PAPP-A inhibitors, stanniocalcin 1 and 2, prevent IGFBP-4 proteolysis and inhibit IGF1R activation (49). Like the other IGFBPs, IGFBP-3 can bind IGFs with high affinity to inhibit IGF1R activation. IGFBP-3 can also activate a phosphotyrosine phosphatase that reverses IGF-activated IGF1R signaling (50). IGFBP-3, acting through TGFβ receptor type V (LRP1), also activates the Ser/Thr phosphoprotein phosphatase PP2A (also see Fig. 3) (51). PP2A interaction with IGF1R through the adapter protein RACK1 is associated with signaling inhibition but can be reversed by IGF stimulation and β-integrin ligation (52). Abbreviations: IGF, insulin-like growth factor; IGF1R, insulin-like growth factor 1 receptor; IGFBP, insulin-like growth factor binding protein; PAPP-A, pregnancy-associated plasma protein; PP2A, phosphoprotein phosphatase 2A; Ser/Thr, serine/threonine; TGFβ, transforming growth factor β.

Figure 2.

IGFBP potentiation of IGF1R signaling. Dephosphorylation of IGFBP-1 decreases its IGF affinity, increasing IGF activation of IGF1R (77). IGFBP-3 activates sphingosine kinase, which phosphorylates sphingosine to S1P. S1P activates the G-protein coupled receptors S1P₁ and S1P₃ leading to IGF1R transactivation, probably mediated by EGFR (78). IGFBP-2 amplifies IGF1R signaling by binding to the protein tyrosine phosphatase RPTPβ, promoting IGF-dependent PKCζ phosphorylation of VIM, which binds to RPTPβ and inactivates it. This inhibits PTEN activity, which enhances IGF-dependent IGF1R signaling [adapted from (79)]. See (79) for further details of the signaling complex. IGFBP-5 and possibly other IGFBPs can enhance IGF1R activation by binding to ECM, which lowers its IGF binding affinity, acting as a reservoir to enhance IGF availability (80). Abbreviations: ECM, extracellular matrix; EGFR, epidermal growth factor receptor; IGF, insulin-like growth factor; IGF1R, insulin-like growth factor 1 receptor; IGFBP, insulin-like growth factor binding protein; PKCζ, protein kinase C zeta; PTEN, phosphatase and tensin homologue; RPTPβ, receptor protein tyrosine phosphatase beta; VIM, vimentin.

Figure 3.

IGF1R-independent IGFBP signaling from the cell surface. IGFBP-1 and IGFBP-2 activate α₅β₁ integrin signaling through their RGD motif. IGFBP-1 can activate FAK-RhoA (100), and IGFBP-2 is reported to signal through both FAK (104) and ILK-NFκB (103). IGFBP-3 can activate apoptosis and other functions through the TMEM219 (113), stimulate SMAD signaling through the TGFβ receptors TβRI/TβRII (114), and inhibit proliferation through TβRV (LRP1) and PP2A activation (also see Fig. 1) (51). IGFBP-4 can block Wnt pathway signaling stimulated by Wnt3A or the receptors LRP6 or Frz8 (115) but in another system promotes Wnt/β-catenin signaling and TCF transcription (116). Despite lacking a recognized integrin-binding motif, IGFBP-5 can signal through α₂β₁ integrin, upregulating ILK and activating Akt (109). IGFBP-6 can signal from the cell surface through PHB2 and another unknown protein to activate ERK, p38, and JNK MAP kinases (117). See text for other IGF1R-independent IGFBP signaling. Abbreviations: ERK, extracellular signal-regulated kinase; FAK, focal adhesion kinase; IGF1R, insulin-like growth factor 1 receptor; IGFBP, insulin-like growth factor binding protein; ILK, integrin-linked kinase; JNK, c-Jun NH₂-terminal kinase; MAP, mitogen-activated protein; NF-κB, nuclear factor kappa B; PHB2, prohibitin-2; PP2A, phosphoprotein phosphatase 2A; RGD, arginine-glycine-aspartic acid; RhoA, Ras homolog family member A; TβRV, transforming growth factor β receptor V; TCF, T-cell factor; TGFβ, transforming growth factor β; TMEM219, transmembrane protein 219.

Figure 4.

IGF1R-independent IGFBP signaling in the nucleus. (A) IGFBP-3 promotes DNA damage repair by NHEJ after translocating with EGFR from the cell surface to the nucleus (139). In a complex with the RNA-binding proteins SFPQ and NONO, it is required for DNA-PKcs activation in response to DNA double-strand breaks. The involvement of long noncoding RNA(s) in this process has also been proposed (140). Similarly, IGFBP-2 enhances the nuclear translocation of EGFR and promotes both EGFR and DNA-PKcs phosphorylation (141). IGFBP-6 can also modulate DNA repair through interaction with the NHEJ complex proteins, Ku70/Ku80, but appears to inhibitory to NHEJ (142). (B) IGFBP-3 interacts with, and modulates the transcriptional effects of, the nuclear receptor RXRα as well as its heterodimerization partners Nur77, RARα, PPARγ, VDR, and TRα1. In similar mechanisms, IGFBP-5 binds and modulates RXRα and VDR and IGFBP-6 interacts with VDR and TRα1 (see Table 2). (C). IGFBP-2, -3 and -5 have defined transactivation domains in their N-terminal regions (153) potentially enabling DNA interactions that may also involve other DNA-binding factors; for example, IGFBP-2 interacts with the VEGF promoter to induce VEGF (138), possibly involving the transcription factor FRA-1 (154). See text for other examples. Abbreviations: EGFR, epidermal growth factor receptor; IGF1R, insulin-like growth factor 1 receptor; IGFBP, insulin-like growth factor binding protein; NHEJ, nonhomologous end-joining; PKcs, protein kinase catalytic subunit; PPARγ, peroxisome proliferator activated receptor-γ; RARα, retinoic acid receptor-α; RXRα, retinoid X receptor-α; TRα1, thyroid hormone receptor-α; VEGF, vascular endothelial growth factor; VDR, vitamin D receptor.