The pathway mediating insulin's effects on pyruvate dehydrogenase bypasses the insulin receptor tyrosine kinase.
The effect of insulin on pyruvate dehydrogenase activity was examined in two different cell types that over expressed either normal or defective human insulin receptors, RAT 1 embryonic fibroblasts and Chinese hamster ovary (CHO) cells. Insulin stimulated pyruvate dehydrogenase activity in cells that expressed normal insulin receptors (RAT 1 HIRc, and CHO-WT and CHO-T cells), or receptors in which lysine 1018 in the ATP-binding site of the tyrosine kinase domain was exchanged for alanine (RAT 1 A/K1018 and CHO-mut cells). For both rat and hamster cell lines, the insulin dose-response curves from cells that expressed the mutant receptors were identical to those from the appropriate controls that over expressed the normal insulin receptors. Insulin failed to stimulate pyruvate dehydrogenase activity in CHO-delta cells, which expressed a mutant human insulin receptor that was truncated by 112 amino acids at the carboxyl terminal of the beta chain. Control studies verified that all the cells used in this study exhibited the expected phenotypes with respect to the number of insulin receptors which they expressed, insulin-stimulated tyrosine kinase activity, and the biological consequences of inactivating the insulin receptor tyrosine kinase. These findings show that the insulin receptor tyrosine kinase does not play an obligatory role in the insulin signaling pathway that stimulates pyruvate dehydrogenase activity.
Gottschalk
W K
WK
Department of Biochemistry, University of Tennessee, Memphis 38163.
D000818:Animals; D006224:Cricetinae; D004789:Enzyme Activation; D005947:Glucose / Q000378:metabolism; D006003:Glycogen / Q000096:biosynthesis; D006801:Humans; D066298:In Vitro Techniques; D007328:Insulin / Q000494:pharmacology*; D009842:Oligopeptides / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism*; D051381:Rats; D011972:Receptor, Insulin / Q000502:physiology*; D011994:Recombinant Proteins; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D014162:Transfection
D007328:Insulin; D009842:Oligopeptides; D011768:Pyruvate Dehydrogenase Complex; D011994:Recombinant Proteins; C037642:kemptide; D006003:Glycogen; D011505:Protein-Tyrosine Kinases; D011972:Receptor, Insulin; D005947:Glucose