Cellular expression of mutant insulin receptors interferes with the rapid transcriptional response to both insulin and insulin-like growth factor I.

We examined the expression of the proto-oncogene c-fos and the early growth response gene, Egr-1, in Rat 1 fibroblasts expressing high levels of normal or mutated human insulin receptors (McClain, D. A., Maegawa, H., Lee, J., Dull, T. J., Ullrich, A., and Olefsky, J. M. (1987) J. Biol. Chem. 262, 14663-14671). In cells expressing large numbers of normal human insulin receptors (HIRc-B cells), insulin (greater than or equal to 0.7 nM) stimulated the rapid accumulation of mRNAs for both genes. This response was blunted, but not lost, in cells expressing large numbers of human insulin receptors missing 43 amino acids at the carboxyl terminus of the beta-subunit. In contrast, the insulin response was completely absent in cells expressing large numbers of receptors that contained a mutation at the ATP-binding site that destroyed intrinsic protein tyrosine kinase activity (A/K 1018-B cells). This mutation also suppressed the modest transcriptional response to insulin that occurred in the parental Rat 1 cells. The transcriptional response to serum was normal in the A/K 1018-B cells, even after protein kinase C depletion; however, the response to insulin-like growth factor I was essentially lost. These studies suggest that overexpression of a kinase-deficient insulin receptor can suppress the transcriptional response to both insulin and insulin-like growth factor I that is ordinarily transduced through endogenous insulin and insulin-like growth factor I receptors, respectively. Competition for shared substrates of these related receptor kinases is a potential mechanism for this effect.