Vila-Coro A J, Rodríguez-Frade J M, Martín De Ana A, Moreno-Ortíz M C, Martínez-A C, Mellado M
Department of Immunology and Oncology, Centro Nacional de Biotecnología, CSIC-Universidad Autónoma de Madrid, Campus de Cantoblanco, E-28049 Madrid, Spain.
FASEB J. 1999 Oct;13(13):1699-710.
The chemokine stromal cell-derived factor (SDF-1alpha), 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-1alpha binding in human T cell lines. Here we demonstrate that SDF-1alpha activation promotes the physical association of Galpha(i) with the CXCR4. Furthermore, within seconds of SDF-1alpha activation, the CXCR4 receptor becomes tyrosine phosphorylated through the activation and association with the receptor of JAK2 and JAK3 kinases. After SDF-1alpha binding, JAK2 and JAK3 associate with CXCR4 and are activated, probably by transphosphorylation, in a Galpha(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-1alpha-induced activation and association of the tyrosine phosphatase Shp1 with the CXCR4 in a Galpha(i)-dependent manner. As occurs with the cytokine receptors in response to cytokines, the CXCR4 undergoes receptor dimerization after SDF-1alpha 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.
趋化因子基质细胞衍生因子（SDF - 1α）是CXCR4受体的配体，可诱导多种效应，包括钙动员、趋化反应、骨髓髓系造血、神经元模式形成以及预防HIV - 1感染。尽管如此，对于受体 - 趋化因子相互作用后引发的这种多样反应所需的生化途径却知之甚少。我们开发了一组特异性识别CXCR4受体的单克隆抗体，并利用它们来鉴定人T细胞系中SDF - 1α结合后激活的信号通路。在此我们证明，SDF - 1α激活促进Gα(i)与CXCR4的物理结合。此外，在SDF - 1α激活后的数秒内，CXCR4受体通过与JAK2和JAK3激酶的激活及结合而发生酪氨酸磷酸化。SDF - 1α结合后，JAK2和JAK3与CXCR4结合并被激活，可能是通过转磷酸化，且不依赖于Gα(i)。这种激活使得转录因子STAT家族的几个成员被招募并发生酪氨酸磷酸化。最后，我们还观察到SDF - 1α以Gα(i)依赖的方式诱导酪氨酸磷酸酶Shp1与CXCR4的激活及结合。如同细胞因子受体对细胞因子的反应一样，SDF - 1α结合后CXCR4会发生受体二聚化，这是触发生物学反应的关键步骤。我们提供了令人信服的证据，表明趋化因子通过与细胞因子激活的机制相似的机制进行信号传导。
