Replacement of Insulin Receptor Tyrosine Residues 1162 and 1163 Does not Alter the Mitogenic Effect of the Hormone

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 85; no. 21; pp. 8032 - 8036
• Main Authors: Debant, Anne, Clauser, Eric, Ponzio, Gilles, Filloux, Chantal, Auzan, Colette, Contreres, Jean-Olivier, Rossi, Bernard
• Format: Journal Article
• Language: English
• Published: Washington, DC National Academy of Sciences of the United States of America 01-11-1988; National Acad Sciences
• Subjects: 550201 - Biochemistry- Tracer Techniques; ALDEHYDES; AMINO ACIDS; ANIMAL CELLS; Animals; AZINES; BASIC BIOLOGICAL SCIENCES; Biological and medical sciences; CARBOHYDRATES; CARBOXYLIC ACIDS; Cell growth; Cell Line; Cell lines; Cell physiology; CELL PROLIFERATION; Cells; CHEMICAL REACTIONS; CHO CELLS; Cricetinae; Deoxyglucose - pharmacokinetics; DNA REPLICATION; DNA Replication - drug effects; ENZYME ACTIVITY; ENZYMES; Fundamental and applied biological sciences. Psychology; Genetic mutation; GLUCOSE; Glycogen; HETEROCYCLIC COMPOUNDS; HEXOSES; Hormonal regulation; HORMONES; HYDROGEN COMPOUNDS; HYDROXY ACIDS; INHIBITION; INSULIN; MEMBRANE PROTEINS; mitogenesis; MITOGENS; Molecular and cellular biology; MONOSACCHARIDES; MUTATIONS; NUCLEIC ACID REPLICATION; NUCLEOSIDES; NUCLEOTIDES; ORGANIC ACIDS; ORGANIC COMPOUNDS; ORGANIC NITROGEN COMPOUNDS; PEPTIDE HORMONES; PHENYLALANINE; PHOSPHORUS-GROUP TRANSFERASES; PHOSPHORYLATION; PHOSPHOTRANSFERASES; Protein Kinases - metabolism; PROTEINS; PYRIMIDINES; Receptor, Insulin - analysis; RECEPTORS; RIBOSIDES; Ribosomal Protein S6 Kinases; SACCHARIDES; Solubility; THYMIDINE; TRANSFERASES; TRITIUM COMPOUNDS; TYROSINE; Tyrosine - analysis; UPTAKE; Tyrosine; Protein hormone; Pancreatic hormone; Substitution; Mitosis; Aminoacid; Insulin; Biological activity; Hormonal receptor
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.85.21.8032

Chinese hamster ovary transfectants that express insulin receptors in which tyrosine residues 1162 and 1163 were replaced by phenylalanine exhibit a total inhibition of the insulin-mediated tyrosine kinase activity toward exogenous substrates [histone, casein, and poly(Glu/Tyr)]; this latter activity is associated with total inhibition of the hypersensitivity reported for insulin in promoting 2-deoxyglucose uptake. We now present evidence that the twin tyrosines also control the insulin-mediated stimulation of glycogen synthesis. Surprisingly, this type of Chinese hamster ovary transfectant is as hypersensitive to insulin for its mitogenic effect as are Chinese hamster ovary cells expressing many intact insulin receptors. Such data suggest that (i) the insulin mitogenic effect routes through a different pathway than insulin uses to activate the transport and metabolism of glucose and (ii) the mitogenic effect of insulin is not controlled by the twin tyrosines. At the molecular level, the solubilized mutated receptor has no insulin-dependent tyrosine kinase activity, whereas this receptor displays measurable insulin-stimulated phosphorylation of its β subunit in 32P-labeled cells. We therefore propose that the autocatalytic phosphorylating activity of the receptor reports a cryptic tyrosine kinase activity that cannot be visualized by the use of classical exogenous substrates.