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J. Biol. Chem., Vol. 281, Issue 51, 39542-39549, December 22, 2006

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The G₁₃-Rho Signaling Axis Is Required for SDF-1-induced Migration through CXCR4^*

From the Oral and Pharyngeal Cancer Branch, NIDCR, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892-4330

The CXC chemokine stromal cell-derived factor-1 (SDF-1) binds to CXCR4, a seven-transmembrane G protein-coupled receptor that plays a critical role in many physiological processes that involve cell migration and cell fate decisions, ranging from stem cell homing, angiogenesis, and neuronal development to immune cell trafficking. CXCR4 is also implicated in various pathological conditions, including metastatic spread and human immunodeficiency virus infection. Although SDF-1-induced cell migration in CXCR4-expressing cells is sensitive to pertussis toxin treatment, hence involving heterotrimeric G proteins of the G_i family, whether other G proteins participate in the chemotactic response to SDF-1 is still unknown. In this study, we took advantage of the potent chemotactic activity of SDF-1 in Jurkat T-cells to examine the nature of the heterotrimeric G protein subunits contributing to CXCR4-mediated cell migration. We observed that whereas G_i and G subunits are involved in SDF-1-induced Rac activation and cell migration, CXCR4 can also stimulate Rho potently leading to the phosphorylation of myosin light chain through the Rho effector, Rho kinase, but independently of G_i. Furthermore, we found that G₁₃ mediates the activation of Rho by CXCR4 and that the functional activity of both G₁₃ and Rho is required for directional cell migration in response to SDF-1. Collectively, our data indicate that signaling by CXCR4 to Rho through G₁₃ contributes to cell migration when stimulated by SDF-1, thus identifying the G₁₃-Rho signaling axis as a potential pharmacological target in many human diseases that involve the aberrant function of CXCR4.

Received for publication, September 25, 2006

^* This work was supported by the Intramural Research Program of the National Institutes of Health, NIDCR. 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 To whom correspondence should be addressed: Oral and Pharyngeal Cancer Branch, NIDCR, National Institutes of Health, 30 Convent Dr., Bldg. 30, Rm. 211, Bethesda, MD 20892-4340. Tel.: 301-496-6259; Fax: 301-402-0823; E-mail: sg39v{at}nih.gov.

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