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

FASEB J. 1999 Oct;13(13):1699-710.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biological Transport
  • Cell Nucleus / metabolism
  • Chemokine CXCL12
  • Chemokines, CXC / metabolism*
  • Cytoplasm / metabolism
  • 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 / metabolism*
  • Proto-Oncogene Proteins*
  • Receptors, CXCR4 / metabolism*
  • Signal Transduction
  • Transcription Factors / metabolism*
  • Virulence Factors, Bordetella / pharmacology

Substances

  • CXCL12 protein, human
  • Chemokine CXCL12
  • Chemokines, CXC
  • Proto-Oncogene Proteins
  • Receptors, CXCR4
  • Transcription Factors
  • Virulence Factors, Bordetella
  • Protein-Tyrosine Kinases
  • JAK2 protein, human
  • JAK3 protein, human
  • Janus Kinase 2
  • Janus Kinase 3
  • Protein Tyrosine Phosphatases
  • GTP-Binding Protein alpha Subunits, Gi-Go