Insulin-Like Growth Factor II (IGF-II) and the IGF-II/ Mannose-6-Phosphate Receptor: The Myth Continues

Insulin-like growth factor II (IGF-II) is a polypeptide hormone with structural and functional homology with IGF-I and pro-insulin. It is now thought that IGF-II acts as a growth factor during fetal life and development. In rats, IGF-II levels in the circulation are high in the fetus and decline rapidly after birth. IGF-II mRNA expression in many tissues including the liver and the choroids plexus is also high during fetal life and low thereafter. Targeted disruption of the IGF-II gene in mice leads to a deficiency in their growth. Alternatively, it has been proposed that IGF-II could act as a growth and differentiation factor in the central nervous system. Administration of IGF-II into the central nervous system in rats leads to increased food intake and altered feeding behaviour. In muscle cells and in colon epithelial cells, IGF-II might also serve as an important regulator of differentiation, A key role for IGF-II as a paracrine or autocrine growth factor in certain tumours has been proposed. The IGFs exert their effects by binding to high-affinity membrane receptors that are expressed in many cells and tissues. The IGF-I receptor, which binds IGF-I with the highest affinity and which is very similar to the insulin receptor, is thought to mediate most, if not all, of the IGF-induced biological functions. The IGF-II/ mannose-6-phosphate (M6P) receptor is a bifunctional glycoprotein with no homology to the insulin receptor. This receptor binds IGF-II and lysosomal enzymes bearing the M6P recognition marker at distinct binding sites. The receptor serves to target lysosomal enzymes to lysosomes and thus plays a key role in the degradative system of the cell. The IGF-II and the IGF-II/M6P receptor genes are parentally imprinted in the mouse and in humans; while IGF-II seems to be paternally imprinted, the receptor gene is maternally imprinted. Relaxation or loss of imprinting has recently been recognized as a putative epigenetic mutational mechanism in carcinogenesis. It is now clear that both IGF-II and the IGF-II/M6P receptor are important regulators of growth and development in fetal life, during oncogenesis and possibly during differentiation and tissue remodelling.