Potentiation of Rho-A-mediated Lysophosphatidic Acid Activity by Hyperinsulinemia

• Published in: The Journal of biological chemistry Vol. 275; no. 41; pp. 31792 - 31797
• Main Authors: Chappell, James, Golovchenko, Inga, Wall, Kei, Stjernholm, Richard, Leitner, J. Wayne, Goalstone, Marc, Draznin, Boris
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13.10.2000; American Society for Biochemistry and Molecular Biology
• Subjects: Alkyl and Aryl Transferases - antagonists & inhibitors; Alkyl and Aryl Transferases - metabolism; Breast Neoplasms; DNA-Binding Proteins - physiology; Dose-Response Relationship, Drug; Drug Synergism; Enzyme Activation - drug effects; Enzyme Inhibitors - pharmacology; Genes, Reporter - genetics; Guanosine Triphosphate - metabolism; Humans; Hyperinsulinism - enzymology; Hyperinsulinism - metabolism; Insulin - pharmacology; Insulin-Like Growth Factor I - pharmacology; Luciferases - genetics; Lysophospholipids - pharmacology; Nuclear Proteins - physiology; Phosphorylation - drug effects; Protein Processing, Post-Translational - drug effects; Response Elements - genetics; rhoA GTP-Binding Protein - metabolism; Serum Response Factor; Transcriptional Activation - drug effects; Tumor Cells, Cultured
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M004798200

We have shown previously that insulin promotes phosphorylation and activation of farnesyltransferase and geranylgeranyltransferase (GGTase) II. We have now examined the effect of insulin on geranylgeranyltransferase I in MCF-7 breast cancer cells. Insulin increased GGTase I activity 3-fold and augmented the amounts of geranylgeranylated Rho-A by 18%. Both effects of the insulin were blocked by an inhibitor of GGTase I, GGTI-286. The insulin-induced increases in the amounts of geranylgeranylated Rho-A resulted in potentiation of the Rho-A-mediated effects of lysophosphatidic acid (LPA) on a serum response element-luciferase construct. Preincubation of cells with insulin augmented the LPA-stimulated serum response element-luciferase activation to 12-fold, compared with just 6-fold for LPA alone (p < 0.05). The potentiating effect of insulin was dose-dependent, inhibited by GGTI-286 and not mimicked by insulin-like growth factor-1. We conclude that insulin activates GGTase I, increases the amounts of geranylgeranylated Rho-A protein, and potentiates the Rho-A-dependent nuclear effects of LPA in MCF-7 breast cancer cells.