The insulin receptor and type I IGF receptor: comparison of structure and function.
The insulin receptor and type I IGF receptor are closely related in structure and function. The receptors are heterotetrameric glycoproteins, of structure alpha beta beta alpha, which are widely distributed in mammalian tissues. A third member of this receptor family has been described, the insulin receptor-related receptor for which a ligand has still to be identified. It has also been demonstrated that the insulin receptor and IGF receptor form alpha beta beta alpha hybrids in cells expressing both receptors. The key elements in the function of any receptor are recognition of ligand and transmission of an intracellular signal. In the insulin and IGF receptors, determinants of binding specificity are contained within amino-terminal and cysteine-rich domains of the extracellular alpha-subunit. Intracellular signalling is dependent on ligand activated tyrosine kinase activity in the transmembrane beta-subunit, which phosphorylates both the receptor itself and the specific substrate insulin receptor substrate-1 (IRS-1). Phosphorylated IRS-1 binds the enzyme phosphatidylinositol 3-kinase and may act as a multivalent docking site for SH2 domains of other proteins involved in signalling. The possibility that some signalling molecules interact directly with the receptors has not been ruled out. The specificity of action of insulin and IGFs in vivo depends on differences between the respective receptors in tissue distribution, ligand binding specificity and intrinsic signalling capacity. However, the detailed aspects of gene and receptor structure which underly these functional differences are still poorly understood. Moreover, the issue of specificity is complicated by the existence of hybrid and atypical receptors, which in principle could bind and respond to both insulin and IGF-I, although the physiological significance of these receptor subtypes is at present unclear.
Siddle
K
K
Department of Clinical Biochemistry, University of Cambridge Addenbrooke's Hospital, U.K.
D000818:Animals; D006801:Humans; D017526:Receptor, IGF Type 1 / Q000737:chemistry / Q000502:physiology; D011972:Receptor, Insulin / Q000737:chemistry / Q000502:physiology; D013329:Structure-Activity Relationship
D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin