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J. Biol. Chem., Vol. 281, Issue 47, 35812-35825, November 24, 2006

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Activation of STAT3 by G_s Distinctively Requires Protein Kinase A, JNK, and Phosphatidylinositol 3-Kinase^*

Andrew M. F. Liu, Rico K. H. Lo¹, Cecilia S. S. Wong, Christina Morris, Helen Wise, and Yung H. Wong²

From the Department of Biochemistry, Molecular Neuroscience Center, and Biotechnology Research Institute, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon and Department of Pharmacology, Faculty of Medicine, the Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China

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_sQ226L (G_sQL), a constitutively active mutant of G_s, to stimulate STAT3 Tyr⁷⁰⁵ and Ser⁷²⁷ phosphorylations in human embryonic kidney 293 cells. Apart from G_sQL, the stimulation of G_s by cholera toxin or 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_s by RNA interference significantly reduced the 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_sQL 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 ₂-adrenergic receptor stimulation. In contrast to the G₁₆-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_s-mediated responses, including STAT3-driven luciferase activation, were resistant to inhibition of phospholipase C. Surprisingly, G_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-mediated activations of STAT3, the stimulatory signal arising from G_s is transduced via multiple signaling pathways. However, unlike the mechanisms employed by G_i and G_14/16, G_s distinctively requires protein kinase A, JNK, and phosphatidylinositol 3-kinase for STAT3 activation.

Received for publication, June 2, 2006 , and in revised form, September 22, 2006.

^* This work was supported in part by the Council of Hong Kong Research Grants HKUST 6120/04M and HKUST 3/03C, the University Committee Grant AoE/B-15/01, and the Hong Kong Jockey Club. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Present address: Dept. of Medicine, The University of Hong Kong, Hong Kong, China.

² Recipient of the Croucher Senior Research Fellowship. To whom correspondence should be addressed. Tel.: 852-2358-7328; Fax: 852-2358-1552; E-mail: boyung{at}ust.hk.

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