Defect in insulin receptor phosphorylation in erythrocytes and fibroblasts associated with severe insulin resistance.
The insulin receptor is a tyrosine-specific protein kinase. Upon binding of the hormone, the kinase is activated resulting in autophosphorylation of the receptor. This kinase activity has been postulated to be an early step in the transmembrane signaling produced by insulin. To evaluate the physiologic relevance of receptor phosphorylation, we have studied insulin binding and autophosphorylation properties using cells from an individual with a variant of the Type A syndrome of severe insulin resistance and acanthosis nigricans. Erythrocytes and cultured fibroblasts from this individual exhibited normal or near normal 125I-insulin binding. Receptors extracted from erythrocytes with Triton X-100 also exhibited normal 125I-insulin binding and competition curves. Despite this, receptors extracted from both erythrocytes and fibroblasts showed a 50% decrease in insulin-stimulated autophosphorylation. Partially purified receptors from the patient's fibroblasts also exhibited a 40% decrease in their ability to phosphorylate exogenous substrates. These data suggest that the insulin resistance in this syndrome is due to a genetic abnormality which impairs insulin receptor phosphorylation and kinase activity and further support the possible role of receptor phosphorylation and kinase activity in insulin action.
D000052:Acanthosis Nigricans / Q000150:complications / Q000378:metabolism; D000293:Adolescent; D002462:Cell Membrane / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism; D004912:Erythrocytes / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000031:analogs & derivatives / Q000378:metabolism; D007333:Insulin Resistance; D007700:Kinetics; D010766:Phosphorylation; D011494:Protein Kinases / Q000097:blood*; D011505:Protein-Tyrosine Kinases; D011972:Receptor, Insulin / Q000378:metabolism*; D013577:Syndrome
D007328:Insulin; C008147:insulin, iodo-; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; D011972:Receptor, Insulin