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

Article

关键词: CELL-DERIVED FACTOR-1;    LYMPHOCYTE CHEMOATTRACTANT;    TYROSINE PHOSPHORYLATION;    SIGNAL-TRANSDUCTION;    MOLECULAR-CLONING;    T-CELLS;    PROTEIN;    KINASE;    SDF-1;    HIV-1;   

DOI  :  10.1096/fasebj.13.13.1699

来源: SCIE

【 摘 要 】

The chemokine stromal cell-derived factor (SDF-1 alpha), 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-1 alpha binding in human T cell lines. Here we demonstrate that SDF-1 alpha activation promotes the physical association of G alpha(i) with the CXCR4, Furthermore, within seconds of SDF-1 alpha activation, the CXCR4 receptor becomes tyrosine phosphorylated through the activation and association with the receptor of JAK2 and JAK3 kinases. After SDF-1 alpha binding, JAK2 and JAK3 associate with CXCR4 and are activated, probably by transphosphorylation, in a G alpha(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-1 alpha-induced activation and association of the tyrosine phosphatase Shp1 with the CXCR4 in a G alpha(i)-dependent 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 evidence that the chemokines signal through mechanisms similar to those activated 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 pathway.

【 授权许可】

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