How does the mitogenic insulin-like growth factor I receptor differ from the metabolic insulin receptor?
Under normal physiological conditions, insulin regulates intermediary metabolism by interacting with insulin receptors in liver, fat and muscle cells. The insulin-like growth factors (IGF-I and IGF-II), on the other hand, are primarily involved in the regulation of growth and development of the whole organism and interact with IGF receptors expressed by most, if not all, tissues of the body. As the insulin and IGF-I receptors are both structurally and functionally similar, one of the fundamental questions in this area of research has been the basis for the distinct pathways of hormone action elicited by insulin and the IGFs. Several features are involved in the divergence of the signalling pathways of insulin and the IGFs. The insulin receptor binds insulin with high affinity, and this specificity is determined by domains lying to the N-terminal and C-terminal sides of the cysteine-rich region in the alpha-subunit. The high-affinity IGF binding by the IGF-I receptor is determined by its cysteine-rich domain. Secondly, the IGF-binding proteins (IGFBPs), of which six have been characterized, bind the IGFs with an affinity higher than that of the IGF receptors. They bind all the circulating IGFs, protect them from degradation and deliver them to the IGF receptors in the target tissues, where they modulate IGF action. As they have no affinity for insulin, insulin is free to interact with its own receptor. Finally, structural differences in the beta-subunits of the insulin and IGF-I receptors may result in divergence of the signal pathways.(ABSTRACT TRUNCATED AT 250 WORDS)
LeRoith
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D
Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892.
Sampson
P C
PC
Roberts
C T
CT
D006801:Humans; D015394:Molecular Structure; D017526:Receptor, IGF Type 1 / Q000737:chemistry / Q000502:physiology*; D011972:Receptor, Insulin / Q000737:chemistry / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin