Activation of STAT3 by G alpha(s) distinctively requires protein kinase A, JNK, and phosphatidylinositol 3-kinase
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香港中文大學研究人員

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摘要Signal transducer and activator of transcription 3 (STAT3) can be stimulated by several G(s)-coupled receptors, but the precise mechanism of action has not yet been elucidated. We therefore examined the ability of G alpha(s)Q226L (G alpha(s)QL), a constitutively active mutant of G alpha(s), to stimulate STAT3 Tyr(705) and Ser(727) phosphorylations in human embryonic kidney 293 cells. Apart from G alpha(s)QL, the stimulation of G alpha(s) by cholera toxin or beta(2)-adrenergic receptor and the activation of adenylyl cyclase by forskolin, (S-p)-cAMP, or dibutyryl-cAMP all promoted both STAT3 Tyr705 and Ser727 phosphorylations. Moreover, the removal of G alpha(s) by RNA interference significantly reduced the beta(2)-adrenergic receptor-mediated STAT3 phosphorylations, denoting its capacity to regulate STAT3 activation by a G protein-coupled receptor. The possible downstream signaling molecules involved were assessed by using specific inhibitors and dominant negative mutants. Induction of STAT3 Tyr705 and Ser727 phosphorylations by G alpha(s)QL was suppressed by inhibition of protein kinase A, Janus kinase 2/3, Rac1, c-Jun N-terminal kinase (JNK), or phosphatidylinositol 3-kinase, and a similar profile was observed in response to beta 2-adrenergic receptor stimulation. In contrast to the G alpha(16)-mediated regulation of STAT3 in HEK 293 cells (Lo, R. K., Cheung, H., and Wong, Y. H. ( 2003) J. Biol. Chem. 278, 52154 - 52165), the G alpha(s)-mediated responses, including STAT3-driven luciferase activation, were resistant to inhibition of phospholipase C beta. Surprisingly, G alpha(s)-mediated phosphorylation at Tyr705, but not at Ser727, was resistant to inhibition of c-Src, Raf-1, and MEK1/2 as well as to the expression of dominant negative Ras. Therefore, as with other G alpha-mediated activations of STAT3, the stimulatory signal arising from G alpha s is transduced via multiple signaling pathways. However, unlike the mechanisms employed by G alpha(i) and G alpha(14/16), G alpha(s) distinctively requires protein kinase A, JNK, and phosphatidylinositol 3-kinase for STAT3 activation.
著者Liu AMF, Lo RKH, Wong CSS, Morris C, Wise H, Wong YH
期刊名稱Journal of Biological Chemistry
出版年份2006
月份11
日期24
卷號281
期次47
出版社AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
頁次35812 - 35825
國際標準期刊號0021-9258
電子國際標準期刊號1083-351X
語言英式英語
Web of Science 學科類別Biochemistry & Molecular Biology; BIOCHEMISTRY & MOLECULAR BIOLOGY

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