Abstract
SDF-1alpha (CXCL12) signaling via its receptor, CXCR4, stimulates T cell chemotaxis and gene expression. The ZAP-70 tyrosine kinase critically mediates SDF-1alpha-dependent migration and prolonged ERK mitogen-activated protein (MAP) kinase activation in T cells. However, the molecular mechanism by which CXCR4 or other G protein-coupled receptors activate ZAP-70 has not been characterized. Here we show that SDF-1alpha stimulates the physical association of CXCR4 and the T cell receptor (TCR) and utilizes the ZAP-70 binding ITAM domains of the TCR for signal transduction. This pathway is responsible for several of the effects of SDF-1alpha on T cells, including prolonged ERK MAP kinase activity, increased intracellular calcium ion concentrations, robust AP-1 transcriptional activity, and SDF-1alpha costimulation of cytokine secretion. These results suggest new paradigms for understanding the effects of SDF-1alpha and other chemokines on immunity.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Antigens, CD / metabolism
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Antigens, Differentiation, T-Lymphocyte / metabolism
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Calcium / metabolism
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Cells, Cultured
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Chemokine CXCL12
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Chemokines, CXC / pharmacology
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Enzyme Activation / drug effects
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Humans
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Interleukin-10 / metabolism
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Interleukin-2 / metabolism
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Lectins, C-Type
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Models, Immunological
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Phosphotyrosine / metabolism
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Protein Binding
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Receptors, Antigen, T-Cell / immunology*
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Receptors, Antigen, T-Cell / metabolism
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Receptors, CXCR4 / immunology*
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Signal Transduction / immunology*
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T-Lymphocytes / drug effects
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T-Lymphocytes / immunology*
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T-Lymphocytes / metabolism
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Transcription Factor AP-1 / metabolism
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Transcriptional Activation / genetics
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ZAP-70 Protein-Tyrosine Kinase / metabolism
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ras Proteins / metabolism
Substances
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Antigens, CD
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Antigens, Differentiation, T-Lymphocyte
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CD69 antigen
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CXCL12 protein, human
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Chemokine CXCL12
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Chemokines, CXC
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Interleukin-2
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Lectins, C-Type
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Receptors, Antigen, T-Cell
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Receptors, CXCR4
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Transcription Factor AP-1
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Interleukin-10
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Phosphotyrosine
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ZAP-70 Protein-Tyrosine Kinase
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ras Proteins
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Calcium