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-1α/CXCL12 chemokine

Kimberly N. Kremer, Troy D. Humphreys, Ashok Kumar, Nan Xin Qian, Karen E. Hedin

Research output: Contribution to journalArticlepeer-review

60 Scopus citations

Abstract

Stimulation of T lymphocytes with the ligand for the CXCR4 chemokine receptor stromal cell-derived factor-1α (SDF-1α/CXCL12), results in prolonged activation of the extracellular signal-regulated kinases (ERK) ERK1 and ERK2. Because SDF-1α is unique among several chemokines in its ability to stimulate prolonged ERK activation, this pathway is thought to mediate special functions of SDF-1α that are not shared with other chemokines. However, the molecular mechanisms of this response are poorly understood. In this study we show that SDF-1α 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-1α-mediated ERK activation. However, neither the SLP-76 proline-rich domain that links to GADS and LAT, nor LAT, itself are required for SDF-1α to stimulate SLP-76 tyrosine phosphorylation or to activate ERK. Together, our results describe the distinct mechanism by which SDF-1α stimulates prolonged ERK activation in T cells and indicate that this pathway is specific for cells expressing both ZAP-70 and SLP-76.

Original languageEnglish (US)
Pages (from-to)360-367
Number of pages8
JournalJournal of Immunology
Volume171
Issue number1
DOIs
StatePublished - Jul 1 2003

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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