**Background:** The insulin-like growth factor (IGF) axis includes IGF-1 and IGF-2, their receptors (IGF1R, IGF2R), and six high-affinity IGF binding proteins (IGFBP-1 to -6). IGFBPs were initially recognized for their role in transporting IGFs and modulating IGF1R signaling by binding IGFs with high affinity, thereby inhibiting or potentiating receptor activation. However, a growing body of evidence demonstrates that IGFBPs also exert numerous IGF-independent effects through interactions with diverse cell-surface and intracellular proteins. This review synthesizes current knowledge of the signaling pathways mediated by IGFBPs, highlighting both IGF-dependent and IGF-independent mechanisms and their implications for cellular functions and disease.
**Methods:** This is a narrative review that synthesizes findings from a wide range of published studies, including cell-based assays, animal models, and clinical observations. The author discusses the structural features of IGFBPs, their post-translational modifications (e.g., phosphorylation, proteolysis), and their interactions with various ligands such as integrins, nuclear receptors, and other signaling molecules. The review covers all six high-affinity IGFBPs and includes data from studies using genetic knockout models, recombinant proteins, and pharmacological inhibitors.
**Key Results:** The review details multiple mechanisms by which IGFBPs modulate IGF1R signaling. For example, hyperphosphorylation of IGFBP-1 at serine residues 101, 119, and 169 increases its affinity for IGF-1, inhibiting IGF1R phosphorylation (Figure 1). Proteolysis of IGFBPs, particularly IGFBP-4 by PAPP-A, reduces binding affinity and releases IGFs to activate IGF1R. Conversely, dephosphorylated IGFBP-1 potentiates IGF1R signaling, and IGFBP-3 can activate sphingosine kinase to generate sphingosine-1-phosphate, which transactivates IGF1R via EGFR (Figure 2). IGF-independent signaling is extensive: IGFBP-1 and IGFBP-2 bind integrin α5β1 via their RGD motifs, activating FAK and downstream pathways (Table 1). IGFBP-3 interacts with TMEM219 to induce autophagy and apoptosis, and with nuclear receptors such as RXRα, Nur77, and VDR to modulate transcription (Table 2). IGFBP-4 can inhibit or stimulate Wnt/β-catenin signaling depending on the cellular context. IGFBP-5 binds integrin α2β1 and activates ILK/Akt, and also interacts with TNFR1 to inhibit NF-κB signaling. IGFBP-6 signals through PHB2 to activate MAP kinases and can inhibit DNA repair by binding Ku80. In cell senescence, IGFBP-3, -4, and -5 promote senescence, while IGFBP-1 and -6 may delay it. In DNA repair, IGFBP-2 and -3 facilitate nonhomologous end-joining (NHEJ) by interacting with EGFR and DNA-PKcs, whereas IGFBP-6 appears inhibitory. In immune function, IGFBP-3 inhibits CD8+ T cell infiltration into tumors, and IGFBP-6 stimulates T cell migration in rheumatoid arthritis.
**Clinical Implications:** The diverse signaling pathways of IGFBPs offer potential therapeutic targets for various diseases. For instance, the RGD motif of IGFBP-1 has been explored as a therapy for insulin resistance, and a recombinant TMEM219 ectodomain polypeptide protects against hyperglycemia in diabetic mice by blocking IGFBP-3-induced β-cell apoptosis. In cancer, IGFBP-2 and -3 are associated with poor prognosis and chemoresistance, and targeting their interactions with EGFR or DNA-PKcs could enhance radiotherapy or chemotherapy efficacy. However, the context-dependent and often opposing effects of IGFBPs (e.g., pro- vs. anti-apoptotic) complicate therapeutic development. The review emphasizes the need for a deeper understanding of post-translational modifications and cell-specific factors that govern IGFBP actions to design effective interventions.