Figure. The IGF system. The IGF system is comprised of 3 ligands (insulin, IGF-I, and IGF-II), 3 receptors (insulin, IGF-I, and IGF-II/mannose 6-phosphate receptors), and at least 6 IGF-binding proteins (IGFBP1-6). Naturally occurring hybrid receptors have been described in which an insulin /β hemireceptor is linked to an IGF-I /β hemireceptor. The black area in the receptor cytoplasmic region denotes the tyrosine kinase domain. The IGF-II/mannose 6-phosphate receptor is a single-chain polypeptide composed of 15 repeat sequences and a short cytoplasmic domain. IGF-I and IGF-II circulate in blood and extracellular space linked to a family of binding proteins. IGFBP3 is the most abundant BP in serum, and it appears as a ternary complex that includes the ligand and an acid-labile subunit (ALS). IGFBP proteases have been described that cleave IGFBPs, thus modulating the bioavailability of IGF ligands. IGFBP6 exhibits a particularly high affinity for IGF-II.