Regulation of cytotoxic T lymphocyte-associated molecule-4 by Src kinases

Ellen Chuang, Kyung-Mi Lee, Michael D. Robbins, James M. Duerr, Maria Luisa Alegre, John E. Hambor, Mark J. Neveu, Jeffrey A. Bluestone, Craig B. Thompson

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Abstract

Cytotoxic T lymphocyte-associated molecule-4 (CTLA-4) is a cell surface receptor expressed to activated T cells that can inhibit T cell responses induced by activation of the TCR and CD28. Studies with phosphorylated peptides based on the CTLA-4 intracellular domain have suggested that tyrosine phosphorylation of CTLA-4 may regulate its interactions with cytoplasmic proteins that could determine its intracellular trafficking and/or signal transduction. However, the kinase(s) that phosphorylate CTLA-4 remain uncharacterized. In this report, we show that CTLA-4 can associate with the Src kinases Fyn and Lck and that transfection of Fyn or Lck, but not the unrelated kinase ZAP70, can induce tyrosine phosphorylation of CTLA-4 on residues Y201 and Y218. A similar pattern of tyrosine phosphorylation was found in pervanadate-treated Jurkat T cells stably expressing CTLA-4. Phosphorylation of CTLA-4 Y201 in Jurkat cells correlated with cell surface accumulation of CTLA-4. CTLA-4 phosphorylation induced the association of CTLA-4 with the tyrosine phosphatase SHP-2, but not with phosphatidylinositol 3-kinase. In contrast, Lck-induced phosphorylation of CD28 resulted in the recruitment of phosphatidylinositol 3-kinase, but not SHP-2. These findings suggest that phosphorylation of CD28 and CTLA-4 by Lck activates distinct intracellular signalling pathways. The association of CTLA-4 with Src kinases and with SHP-2 results in the formation of a CTLA-4 complex with the potential to regulate T cell activation.

Original languageEnglish
Pages (from-to)1270-1277
Number of pages8
JournalJournal of Immunology
Volume162
Issue number3
Publication statusPublished - 1999 Feb 1
Externally publishedYes

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ASJC Scopus subject areas

  • Immunology

Cite this

Chuang, E., Lee, K-M., Robbins, M. D., Duerr, J. M., Alegre, M. L., Hambor, J. E., Neveu, M. J., Bluestone, J. A., & Thompson, C. B. (1999). Regulation of cytotoxic T lymphocyte-associated molecule-4 by Src kinases. Journal of Immunology, 162(3), 1270-1277.