The chemokine SDF‐lα triggers CXCR4 receptor dimerization and activates the JAK/STAT pathway

Abstract

The chemokine stromal cell‐derived factor (SDF‐1α), the ligand for the CXCR4 receptor, induces a wide variety of effects that include calcium mobilization, chemotactic responses, bone marrow myelopoiesis, neuronal patterning, and prevention of HIV‐1 infection. Nonetheless, little is known of the biochemical pathways required to achieve this variety of responses triggered 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‐1α binding in human T cell lines. Here we demonstrate that SDF‐1α activation promotes the physical association of Gα i with the CXCR4. Furthermore, within seconds of SDF‐1α activation, the CXCR4 receptor becomes tyrosine phosphorylated through the activation and association with the receptor of JAK2 and JAK3 kinases. After SDF‐1α binding, JAK2 and JAK3 associate with CXCR4 and are activated, probably by transphosphorylation, in a Gα i ‐independent manner. This activation enables the recruitment and tyrosine phosphorylation of several members of the STAT family of transcription factors. Finally, we have also observed SDF‐1α‐induced activation and association of the tyrosine phosphatase Shpl with the CXCR4 in a Gα i ‐dependent manner. As occurs with the cytokine receptors in response to cytokines, the CXCR4 undergoes receptor dimerization after SDF‐1α binding and is a critical step in triggering biological responses. We present compelling evidence that the chemokines signal through mechanisms similar to those activated by cytokines.—Vila‐Coro, A. J., Rodríguez‐Frade, J. M., Martín de Ana, A., Moreno‐Ortíz, M. C., Martínez‐A., C., Mellado, M. The chemokine SDF‐1 α triggers CXCR4 receptor dimerization and activates the JAK/STAT pathway. FASEB J . 13, 1699–1710 (1999)