The chemokine SDF-1 alpha triggers CXCR4 receptor dimerization and activates the JAK/STAT pathway

The chemokine stromal cell-derived factor (SDF-1 alpha), the ligand for the CXCR4 receptor, induces a wide variety of effects that include calcium mob ilization, chemotactic responses, bone marrow myelopoiesis, neuronal patter ning, and prevention of HIV-1 infection. Nonetheless, little is known of th e biochemical pathways required to achieve this variety of responses trigge red after receptor- chemokine interaction. We developed a set of monoclonal antibodies that specifically recognize the CXCR4 receptor and used them to identify the signaling pathway activated after SDF-1 alpha binding in huma n T cell lines. Here we demonstrate that SDF-1 alpha activation promotes th e physical association of G alpha(i) with the CXCR4, Furthermore, within se conds of SDF-1 alpha activation, the CXCR4 receptor becomes tyrosine phosph orylated through the activation and association with the receptor of JAK2 a nd JAK3 kinases. After SDF-1 alpha binding, JAK2 and JAK3 associate with CX CR4 and are activated, probably by transphosphorylation, in a G alpha(i)-in dependent manner. This activation enables the recruitment and tyrosine phos phorylation of several members of the STAT family of transcription factors. Finally, we have also observed SDF-1 alpha-induced activation and associat ion of the tyrosine phosphatase Shp1 with the CXCR4 in a G alpha(i)-depende nt manner, As occurs with the cytokine receptors in response to cytokines, the CXCR4 undergoes receptor dimerization after SDF-1 alpha binding and is a critical step in triggering biological responses. We present compelling e vidence that the chemokines signal through mechanisms similar to those acti vated by cytokines.-Vila-Coro, A. J., Rodriguez-Frade, J. M., Martin de Ana , A., Moreno-Ortiz, M. C., Martinez-A., C., Mellado, M. The chemokine SDF-1 alpha triggers CXCR4 receptor dimerization and activates the JAK/STAT path way.