The Gα13-Rho Signaling Axis Is Required for SDF-1-induced Migration through CXCR4

Abstract The CXC chemokine stromal cell-derived factor-1α (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 Gi 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 Gi and Gβγ 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 Gi. Furthermore, we found that Gα13 mediates the activation of Rho by CXCR4 and that the functional activity of both Gα13 and Rho is required for directional cell migration in response to SDF-1. Collectively, our data indicate that signaling by CXCR4 to Rho through Gα13 contributes to cell migration when stimulated by SDF-1, thus identifying the Gα13-Rho signaling axis as a potential pharmacological target in many human diseases that involve the aberrant function of CXCR4.