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triggers CXCR4 receptor dimerization and activates the JAK/STAT pathway
Department of Immunology and Oncology, Centro Nacional de Biotecnología, CSIC-Universidad Autónoma de Madrid, Campus de Cantoblanco, E-28049 Madrid, Spain
1Correspondence: Department of Immunology and Oncology, Centro Nacional de Biotecnología, CSIC, Universidad Autónoma de Madrid, Campus de Cantoblanco, E-28049 Madrid, Spain. E-mail cmartineza{at}cnb.uam.es
The chemokine stromal cell-derived factor (SDF-1
), 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 binding in human T cell lines. Here we demonstrate that
SDF-1 activation promotes the physical association of
Gi with the CXCR4. Furthermore, within seconds of
SDF-1 activation, the CXCR4 receptor becomes tyrosine phosphorylated
through the activation and association with the receptor of JAK2 and
JAK3 kinases. After SDF-1 binding, JAK2 and JAK3 associate with
CXCR4 and are activated, probably by transphosphorylation, in a
Gi-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-induced activation and association of the tyrosine phosphatase
Shp1 with the CXCR4 in a Gi-dependent manner. As occurs
with the cytokine receptors in response to cytokines, the CXCR4
undergoes receptor dimerization after SDF-1 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 triggers CXCR4 receptor dimerization and
activates the JAK/STAT pathway.
Key Words: chemotactic response • tyrosine phosphorylation • Shp1 • G-proteins
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