Three levels of regulation of the IGF-IR pathwayand its components

The three levels of regulation of the IGF-IR pathwayand its components. A, systemic regulation at the endocrine level. The GH-IGF-IGFBP axis is directed by the hypophysis where GH is produced. In the liver, GH stimulates the secretion of its main effector, IGF-I, as well as IGF-II and IGFBPs. B, at the tissue level, the levels of the free ligands (IGF-I and IGF-II) are regulated bythe presence of the six different IGFBPs, which bind the growth factors with high affinity, and by IGFBP-related proteins, which bind IGF-I and IGF-II with lower affinity. The formers are regulated by specific proteases. Insulin, IGF-I, and IGF-II bind to the different receptors (insulin receptors A and B, IGF-IR, and IGF-IIR) with diverse affinities, and each receptor triggers different intracellular signaling cascades. Hybrid receptors are composed by one α-subunit and one β-subunit of the IGF-IR and one α-subunit and one β-subunit of the insulin receptor. C, at the cellular level, binding of IGF-I to its receptor triggers the autophosphorylation of the later and of the adaptor proteins IRS1 to 4 and shc/ Grb-2. Activation of each of these proteins prompts different signaling cascades through the phosphatidylinositol 3-kinase/Akt and ras/raf/mitogen-activated protein/extracellular signal-regulated kinase kinase pathways. The GH-IGF-IGFBP axis controls, through these three levels of regulation, mediators of the cell cycle, apoptosis, and translation that regulate cell growth, proliferation, and differentiation, as well as energetic metabolism. D, overlapping in function between IGF-IR and IR signaling. I, in normal conditions, both pathways complement each other and there is an equilibrium in signaling between the energy and metabolic pathways and pathways that drive growth and proliferation. II, in tumor cells, IGF-IR signaling is frequently overactive, and the signaling predominance of IGF-IR turns the cells to survive apoptotic signals and to proliferate. III, specific inhibition of IGF-IR with monoclonal antibodies can switch the equilibrium toward a predominance of the insulin pathway, having significant metabolic effects. IV, tyrosine kinase inhibitors differ in specificity against IGF-IR and IR, and each drug has a different profile of toxicity-efficacy. GHRH, growth hormone releasing factor; IGFBP-rP, IGFBP-related proteins; IR-A, insulin receptor A; IR-B, insulin receptor B; PI3K, phosphatidylinositol-3-kinase; Shc, src homology 2 domain-containing.

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Early drug development of inhibitors of the insulin-like growth factor-I receptor pathway: Lessons from the first clinical trials. () Jordi Rodon, et al. Mol Cancer Ther. ;7(9):2575-2588. Figure: F1. All organisms Mus musculus Homo sapiens Drosophila melanogaster

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