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The Journal of Immunology, 2003, 171: 360-367.
Copyright © 2003 by The American Association of Immunologists

Distinct Role of ZAP-70 and Src Homology 2 Domain-Containing Leukocyte Protein of 76 kDa in the Prolonged Activation of Extracellular Signal-Regulated Protein Kinase by the Stromal Cell-Derived Factor-1{alpha}/CXCL12 Chemokine1

Kimberly N. Kremer, Troy D. Humphreys, Ashok Kumar, Nan-Xin Qian and Karen E. Hedin2

Departments of Surgery and Immunology, Mayo Graduate and Medical Schools, Mayo Clinic, Rochester, MN 55905

Stimulation of T lymphocytes with the ligand for the CXCR4 chemokine receptor stromal cell-derived factor-1{alpha} (SDF-1{alpha}/CXCL12), results in prolonged activation of the extracellular signal-regulated kinases (ERK) ERK1 and ERK2. Because SDF-1{alpha} is unique among several chemokines in its ability to stimulate prolonged ERK activation, this pathway is thought to mediate special functions of SDF-1{alpha} that are not shared with other chemokines. However, the molecular mechanisms of this response are poorly understood. In this study we show that SDF-1{alpha} stimulation of prolonged ERK activation in Jurkat T cells requires both the ZAP-70 tyrosine kinase and the Src homology 2 domain-containing leukocyte protein of 76 kDa (SLP-76) scaffold protein. This pathway involves ZAP-70-dependent tyrosine phosphorylation of SLP-76 at one or more of its tyrosines, 113, 128, and 145. Because TCR activates ERK via SLP-76-mediated activation of the linker of activated T cells (LAT) scaffold protein, we examined the role of LAT in SDF-1{alpha}-mediated ERK activation. However, neither the SLP-76 proline-rich domain that links to GADS and LAT, nor LAT, itself are required for SDF-1{alpha} to stimulate SLP-76 tyrosine phosphorylation or to activate ERK. Together, our results describe the distinct mechanism by which SDF-1{alpha} stimulates prolonged ERK activation in T cells and indicate that this pathway is specific for cells expressing both ZAP-70 and SLP-76.




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