Inhibition of insulin receptor activation by insulin-like growth factor binding proteins.
The insulin-like growth factors (IGFs) are transported by a family of high-affinity binding proteins (IGFBPs) that protect IGFs from degradation, limit their binding to IGF receptors, and modulate IGF actions. The six classical IGFBPs have been believed to have no affinity for insulin. We now demonstrate that IGFBP-7/mac25, a newly identified member of the IGFBP superfamily that binds IGFs specifically with low affinity is a high-affinity insulin binding protein. IGFBP-7 blocks insulin binding to the insulin receptor and thereby inhibiting the earliest steps in insulin action, such as autophosphorylation of the insulin receptor beta subunit and phosphorylation of IRS-1, indicating that IGFBP-7 is a functional insulin-binding protein. The affinity of other IGFBPs for insulin can be enhanced by modifications that disrupt disulfide bonds or remove the conserved COOH terminus. Like IGFBP-7, an NH2-terminal fragment of IGFBP-3 (IGFBP-3((1-87))), also binds insulin with high affinity and blocks insulin action. IGFBPs with enhanced affinity for insulin might contribute to the insulin resistance of pregnancy, type II diabetes mellitus, and other pathological conditions.
Yamanaka
Y
Y
Department of Pediatrics, School of Medicine, Oregon Health Sciences University, Portland, Oregon 97201, USA.
Wilson
E M
EM
Rosenfeld
R G
RG
Oh
Y
Y
D016475:3T3 Cells; D000345:Affinity Labels / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D002352:Carrier Proteins / Q000378:metabolism; D003432:Cross-Linking Reagents / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism; D018969:Insulin-Like Growth Factor Binding Proteins / Q000037:antagonists & inhibitors*; D051379:Mice; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011972:Receptor, Insulin / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism
D000345:Affinity Labels; D002352:Carrier Proteins; D003432:Cross-Linking Reagents; C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins; C526295:Irs1 protein, mouse; D010750:Phosphoproteins; C102529:insulin-like growth factor binding protein-related protein 1; D014443:Tyrosine; D011972:Receptor, Insulin