title: Insulin action in cells expressing truncated or kinase-defective insulin receptors. Dissection of multiple hormone-signaling pathways.
abstract: An attempt has been made to dissect insulin-signaling pathways by means of in vitro mutagenesis of the insulin receptor. Studies of two mutants are reviewed: a COOH-truncated receptor and a mutant of the ATP-binding site that is tyrosine kinase defective. The COOH-truncated receptor has normal insulin binding and normal endocytosis and undergoes autophosphorylation and activation as a kinase in vitro and in vivo. Loss of the COOH-terminal 43 amino acids has, however, impaired the ability of the receptor to signal metabolic events while augmenting its ability to signal mitogenesis. Thus, domains have been partially identified that are separately involved in metabolic and mitogenic signaling, facilitating future studies of these pathways. The kinase-defective receptor is not only biologically inactive, but has a dominant inhibitory effect on the endogenous insulin receptors in the cell. That is, transfected Rat-1 cells carrying defective human receptors still have normally active rat insulin receptors but are incapable of signaling insulin action. The fact that metabolic signaling by insulinlike growth factor I (IGF-I) is intact in these cells allows definition of separate insulin and IGF-I pathways, leading to stimulation of glucose transport. Analysis of dose responsiveness for mitogenesis implies that mitogenic signaling pathways are shared by insulin and IGF-I, however. The utility of these cell lines in defining these pathways is discussed.
authors.affiliation: University of California, San Diego.
authors.forename: D A
authors.initials: DA
authors.lastname: McClain
mesh_terms: D000818:Animals; D002460:Cell Line; D006801:Humans; D007328:Insulin / Q000502:physiology*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction
chemical_list: D007328:Insulin; D011505:Protein-Tyrosine Kinases; D011972:Receptor, Insulin