Signalling pathways of insulin-like growth factors (IGFs) and IGF binding protein-3

Although the insulin-like growth factor (IGF) system is essential for normal growth and development, its dysregulation has been implicated in a range of pathological states. The peptide growth factors IGF-I and IGF-II exert their effects by binding to cell-surface heterotetrameric tyrosine kinase receptors and activating multiple intracellular signalling cascades, leading to changes in the expression of proteins essential for cell proliferation, survival and differentiation. The IGF system comprises multiple ligands, receptors and high-affinity IGF binding proteins (IGFBPs), with added complexity arising from crosstalk between its receptors and other key growth-regulatory pathways such as those activated by steroid hormones, integrins and other receptor tyrosine kinases. The IGFBPs are also increasingly recognised for their intrinsic growth-regulatory activity, and the ability of IGFBP-3 to modulate signalling pathways of nuclear hormone and growth factor receptors, as well as novel receptors, is believed to play a role both in normal physiology and in disease.