Figure 2.

Overview of the intracellular signalling of the IGF system. At the cellular level, IGF-I, IGF-II, and insulin ligands interact with a family of signalling tyrosine kinase receptors: the IGF-IR and the insulin receptor IR, which exists in two alternatively spliced isoforms (IRα and IRβ). IRβ has a high affinity for insulin, whereas IRα has a high affinity for IGF-II. Upon the binding of the ligands to the receptors, a signalling cascade is initiated, resulting in the activation of the PI3K/Akt/mTOR/S6K and Grb2/SOS/Ras/Raf/MEK/ERK pathways. Such a cascade culminates in increased cell proliferation, survival, self-renewal, homeostasis, and metabolism. IGFs in the circulation are transported in combination with IGFBP-3 or -5 and an acid labile sub-unit (ALS) that increases their half-life. IGFs are released from IGFBPs -3 and -5 through the action of proteases. There are six high-affinity IGFBPs [1–6] that can act in either an IGF-dependent or independent manner. IGFBPs can interact with different cell surface molecules to exert their IGF-independent effects—for example, integrin receptors or ‘putative’ IGFBP receptors.