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J. Biol. Chem., Vol. 280, Issue 17, 17275-17285, April 29, 2005

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A Role of STAT3 in Rho GTPase-regulated Cell Migration and Proliferation^*

Marcella Debidda, Lei Wang, Heesuk Zang, Valeria Poli, and Yi Zheng¶

From the Division of Experimental Hematology, Children's Hospital Research Foundation, University of Cincinnati, Cincinnati, Ohio 45229 and Department of Genetics, Biology, and Biochemistry, University of Turin 10126, Turin, Italy

Rho family GTPases and STAT3 act as mediators of cytokine and growth factor signaling in a variety of cellular functions involved in inflammation, tumorigenesis, and development. In the course of searching for their functional connections, we found by using STAT3 knock-out mouse embryonic fibroblasts that RhoA, Rac1, and Cdc42 could cause nonspecific activation of STAT3 promoter-driven luciferase reporter in the absence of STAT3, raising concerns to a body of literature where STAT3 was associated with Rho GTPases based on the reporter system. We also found that although active RhoA, Rac1, and Cdc42 could all mediate Ser-727 and Tyr-705 phosphorylation and nuclear translocation of STAT3, the Rho GTPases were able to induce STAT3 activation independently of the interleukin-6 autocrine pathway, and active RhoA, Rac1, or Cdc42 could not form a stable complex with STAT3 as previously suggested, indicating an unappreciated mechanism of STAT3 activation by the Rho GTPases. The RhoA-induced STAT3 activation partly depended on Rho-associated kinase (ROK) and involved multiple effector signals as revealed by the examination of effector domain mutants of RhoA. Genetic deletion of STAT3 led to a loss of response to RhoA in myosin light chain phosphorylation and actin stress fiber induction but sensitized the cells to RhoA or ROK-stimulated cell migration. STAT3 was required for the RhoA-induced NF-B and cyclin D1 transcription and was involved in NF-B nuclear translocation. Furthermore, loss of STAT3 expression inhibited RhoA-promoted cell proliferation and blocked RhoA or ROK induced anchorage-independent growth. These phenotypic changes in STAT3^–/– cells could be rescued by reconstituting STAT3 gene. Our studies carried out in STAT3 null cells demonstrate unambiguously that STAT3 represents an essential effector pathway of Rho GTPases in regulating multiple cellular functions including actin cytoskeleton reorganization, cell migration, gene activation, and proliferation.

Received for publication, November 22, 2004 , and in revised form, February 1, 2005.

^* This work was supported by National Institutes of Health Grants GM 53943 and GM 60523. 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.

^¶ To whom correspondence should be addressed. Tel.: 513-636-0595; Fax: 513-636-3768; E-mail: yi.zheng{at}chmcc.org.

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