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.
Vila-Coro
A J
AJ
Department of Immunology and Oncology, Centro Nacional de Biotecnología, CSIC-Universidad Autónoma de Madrid, Campus de Cantoblanco, E-28049 Madrid, Spain.
Rodríguez-Frade
J M
JM
Martín De Ana
A
A
Moreno-Ortíz
M C
MC
Martínez-A
C
C
Mellado
M
M
D001692:Biological Transport; D002467:Cell Nucleus / Q000378:metabolism; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D019281:Dimerization; D004789:Enzyme Activation; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D006801:Humans; D053614:Janus Kinase 2; D053616:Janus Kinase 3; D010766:Phosphorylation; D020836:Protein Structure, Quaternary; D017027:Protein Tyrosine Phosphatases; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D019718:Receptors, CXCR4 / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D011518:Proto-Oncogene Proteins; D019718:Receptors, CXCR4; D014157:Transcription Factors; D010566:Virulence Factors, Bordetella; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; C507933:JAK3 protein, human; D053614:Janus Kinase 2; D053616:Janus Kinase 3; D017027:Protein Tyrosine Phosphatases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go