GROWTH-HORMONE AND PROLACTIN STIMULATE TYROSINE PHOSPHORYLATION OF INSULIN-RECEPTOR SUBSTRATE-1, SUBSTRATE-2, AND SUBSTRATE-3, THEIR ASSOCIATION WITH P85 PHOSPHATIDYLINOSITOL 3-KINASE (PI3-KINASE), AND CONCOMITANTLY PI3-KINASE ACTIVATION VIA JAK2 KINASE

Citation
T. Yamauchi et al., GROWTH-HORMONE AND PROLACTIN STIMULATE TYROSINE PHOSPHORYLATION OF INSULIN-RECEPTOR SUBSTRATE-1, SUBSTRATE-2, AND SUBSTRATE-3, THEIR ASSOCIATION WITH P85 PHOSPHATIDYLINOSITOL 3-KINASE (PI3-KINASE), AND CONCOMITANTLY PI3-KINASE ACTIVATION VIA JAK2 KINASE, The Journal of biological chemistry, 273(25), 1998, pp. 15719-15726
Citations number
48
Categorie Soggetti
Biology
ISSN journal
00219258
Volume
273
Issue
25
Year of publication
1998
Pages
15719 - 15726
Database
ISI
SICI code
0021-9258(1998)273:25<15719:GAPSTP>2.0.ZU;2-P
Abstract
Growth hormone (GH) and prolactin (PRL) binding to their receptors, wh ich belong to the cytokine receptor superfamily, activate Janus kinase (JAK) 2 tyrosine kinase, thereby leading to their biological actions. We recently showed that GH mainly stimulated tyrosine phosphorylation of epidermal growth factor receptor and its association with Grb2, an d concomitantly stimulated mitogen-activated protein kinase activity i n liver, a major target tissue. Using specific antibodies, we now show that GH was also able to induce tyrosine phosphorylation of insulin r eceptor substrate (IRS)-1/IRS-8 in liver. In addition, the major tyros ine-phosphorylated protein in anti-p85 phosphatidylinositol 3-kinase ( PI3-kinase) immunoprecipitate from liver of wild-type mice was IRS-l, and IRS-2 in IRS-1 deficient mice, but not epidermal growth factor rec eptor. These data suggest that tyrosine phosphorylation of IRS-1 may b e a major mechanism for GH-induced PIS-kinase activation in physiologi cal target organ of GH, liver. We also show that PRL was able to induc e tyrosine phosphorylation of both IRS-1 and IRS-2 in COS cells transi ently transfected with PRLR and in CHO-PRLR cells. Moreover, we show t hat tyrosine phosphorylation of IRS-3 was induced by both GH and PRL i n COS cells transiently transfected with IRS-3 and their cognate recep tors. By using the JAK2-deficient cell lines or by expressing a domina nt negative JAK2 mutant, we show that JAK2 is required for the GH-and PRL-dependent tyrosine phosphorylation of IRS-1, -2, and -3, Finally, a specific PI3-kinase inhibitor, wortmannin, completely blocked the an ti-lipolytic effect of GH in 3T3 L1 adipocytes. Taken together, the ro le of IRS-1, -2, and -3 in GH and PRL signalings appears to be phospho rylated by JAK2, thereby providing docking sites for p85 PI3-kinase an d activating PI3-kinase and its downstream biological effects.