Stromal cell-derived factor-1α/CXCL12-induced chemotaxis of T cells involves activation of the RasGAP-associated docking protein p62Dok-1

Seiichi Okabe, Seiji Fukuda, Young June Kim, Masaru Niki, Louis M. Pelus, Kazuma Ohyashiki, Pier Paolo Pandolfi, Hal E. Broxmeyer

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

Abstract

Events mediating stromal cell-derived factor-1 (SDF-1α/CXCL12) chemotaxis of lymphocytes are not completely known. We evaluated intracellular signaling through RasGAP-associated protein p62Dok-1 (downstream of tyrosine kinase [Dok-1]) and associated proteins. SDF-1α/CXCL12 stimulated Dok-1 tyrosine phosphorylation and association with RasGAP, adaptor protein p46Nck, and Crk-L in Jurkat T cells. The phosphorylation of Dok-1 was blocked by pretreatment of cells with the src kinase inhibitor PP2. Src kinase family member Lck was implicated. SDF-1α/CXCL12 did not phosphorylate Dok-1 in J.CaM1.6 cells, a Jurkat derivative not expressing Lck, but did phosphorylate Dok-1 in J.CaM1.6 cells expressing Lck. SDF-1α/CXCL12 induced the tyrosine phosphorylation of Pyk2 and the association of Pyk2 with zeta chain-associated protein-70 kilodaltons (Zap-70) and Vav. SDF-1α/CXCL12 enhanced the association of RasGAP with Pyk2. CXCR4-expressing NIH3T3 and Baf3 cells transfected with full-length Dok-1 cDNA were suppressed in their responses to SDF-1α/CXCL12-induced chemotaxis; mitogen-activated protein (MAP) kinase activity was also decreased. Chemotaxis to SDF-1/CXCL12 was significantly enhanced in Dok-1-/- CD4+ and CD8+ splenic T cells. These results implicate Dok-1, Nek, Crk-L, and Src kinases-especially Lck, Pyk2, Zap-70, Vav, and Ras-GAP-in intracellular signaling by SDF-1α/CXCL12, and they suggest that Dok-1 plays an important role in SDF-1α/CXCL12-induced Chemotaxis in T cells.

Original languageEnglish (US)
Pages (from-to)474-480
Number of pages7
JournalBlood
Volume105
Issue number2
DOIs
StatePublished - Jan 15 2005

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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