| Autor: |
Myers MG Jr; Research Division, Joslin Diabetes Center and Harvard Medical School, Boston, Massachusetts 02215, USA. myersmg@joslab.harvard.edu, Mendez R, Shi P, Pierce JH, Rhoads R, White MF |
| Jazyk: |
angličtina |
| Zdroj: |
The Journal of biological chemistry [J Biol Chem] 1998 Oct 09; Vol. 273 (41), pp. 26908-14. |
| DOI: |
10.1074/jbc.273.41.26908 |
| Abstrakt: |
Activation of tyrosine kinases by numerous growth factor and cytokine receptors leads to tyrosine phosphorylation of the insulin receptor substrate (IRS)-proteins. Tyrosine-phosphorylated motifs on the IRS proteins bind to the SH2 domains in proteins that mediate downstream signals, including phosphatidylinositol 3'-kinase, GRB-2, and SHP-2. We investigated the function of the two SHP-2 binding COOH-terminal tyrosines of IRS-1 by replacing them with phenylalanine (IRS-1(FCT)). IRS-1(FCT) failed to bind SHP-2 or mediate its tyrosine phosphorylation during insulin stimulation. Although several reports suggest a critical role for SHP-2 in insulin stimulated mitogen-activated protein kinase activation and cell proliferation, IRS-1(FCT) mediated these effects normally in 32D cells. Indeed, IRS-1(FCT) exhibited increased tyrosine phosphorylation, phosphatidylinositol 3'-kinase binding and activation of protein synthesis in response to insulin. These results suggest that SHP-2 attentuates the phosphorylation and downstream signal transmission of IRS-1 and that the interaction of IRS-1 and SHP-2 is an important regulatory event which attenuates insulin metabolic responses. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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