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Molecular Endocrinology, Vol 8, 682-692, Copyright © 1994 by Endocrine Society

ARTICLES

Hybrid formation between endogenous mouse and transfected human tyrosine kinase-deficient (A/K1018) insulin receptors leads to decreased insulin sensitivity in 3T3-L1 adipocytes

KA Grako, DA McClain and JM Olefsky
Department of Medicine, University of California, San Diego 92161.

Swiss Mouse 3T3-L1 cells provide a unique model for insulin-sensitive primary fat cells. Under defined conditions this fibroblast cell line can be converted to fully differentiated adipocytes, characterized by increased insulin receptor number and induction of adipogenic-specific proteins. 3T3-L1 cells were therefore transfected with the cDNA for the A/K1018 insulin receptor (alanine substituted for lysine at amino acid 1018 in the ATP binding region of the kinase domain). The cell lines in which the dominant inhibitory effects of the A/K1018 receptor had been previously demonstrated [Rat 1 fibroblasts and Chinese Hamster Ovary cells] have relatively few endogenous insulin receptors; however, the 3T3-L1 cell line has about 200,000 insulin receptors when differentiated. In this study we have used this cell line to explore the molecular mechanisms for the dominant inhibitory effect of a tyrosine kinase-defective insulin receptor on insulin action. The A/K1018 receptor was inhibitory in the 3T3-L1 cells as shown by decreased glucose transport. Further, altered differentiation in the transfected cell implicates the insulin receptor as an important downstream regulator in this process. We were able to demonstrate the presence of numerous hybrid receptors, composed of endogenous mouse heterodimers and human kinase-deficient heterodimers in these cells. Trans phosphorylation did occur within these hybrids as evidenced by autophosphorylation of human beta-subunits; however, these hybrids are unable to phosphorylate substrates. These results establish hybrid formation as an important determinant in the dominant negative nature of the A/K1018 insulin receptor.


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