The chemokine SDF-1alpha triggers CXCR4 receptor dimerization and activates the JAK/STAT pathway.
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.
Mesh Terms:
Biological Transport, Cell Nucleus, Chemokine CXCL12, Chemokines, CXC, Cytoplasm, Dimerization, Enzyme Activation, GTP-Binding Protein alpha Subunits, Gi-Go, Humans, Janus Kinase 2, Janus Kinase 3, Phosphorylation, Protein Structure, Quaternary, Protein Tyrosine Phosphatases, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Receptors, CXCR4, Signal Transduction, Transcription Factors, Virulence Factors, Bordetella
Biological Transport, Cell Nucleus, Chemokine CXCL12, Chemokines, CXC, Cytoplasm, Dimerization, Enzyme Activation, GTP-Binding Protein alpha Subunits, Gi-Go, Humans, Janus Kinase 2, Janus Kinase 3, Phosphorylation, Protein Structure, Quaternary, Protein Tyrosine Phosphatases, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Receptors, CXCR4, Signal Transduction, Transcription Factors, Virulence Factors, Bordetella
FASEB J.
Date: Oct. 01, 1999
PubMed ID: 10506573
View in: Pubmed Google Scholar
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