Regulation of cytotoxic T lymphocyte-associated molecule-4 by Src kinases.
Regulation of cytotoxic T lymphocyte-associated molecule-4 by Src kinases.
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DOI：
10.4049/jimmunol.162.3.1270
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发表时间：
1999-02
影响因子：
4.4
通讯作者：
Ellen Chuang;Kyung Mi Lee;Michael D. Robbins;James M. Duerr;Maria-Luisa Alegre;John E. Hambor;Mark Joseph Neveu;J. Bluestone;Craig B. Thompson
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文献类型：
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作者：
Ellen Chuang;Kyung Mi Lee;Michael D. Robbins;James M. Duerr;Maria-Luisa Alegre;John E. Hambor;Mark Joseph Neveu;J. Bluestone;Craig B. Thompson
细胞毒性T淋巴细胞相关分子-4（CTLA-4）是在活化的T细胞上表达的细胞表面受体，其可以抑制由TCR和CD 28活化诱导的T细胞应答。基于CTLA-4胞内结构域的磷酸化肽的研究表明，CTLA-4的酪氨酸磷酸化可以调节其与细胞质蛋白的相互作用，所述细胞质蛋白可以决定其胞内运输和/或信号转导。然而，使CTLA-4磷酸化的激酶仍然未被表征。在这份报告中，我们表明，CTLA-4可以与Src激酶Fyn和Lck和Fyn或Lck的转染，而不是无关的激酶ZAP 70，可以诱导酪氨酸磷酸化的CTLA-4上的残基Y201和Y218。在过钒酸盐处理的稳定表达CTLA-4的Jurkat T细胞中发现了类似的酪氨酸磷酸化模式。Jurkat细胞中CTLA-4 Y201的磷酸化与CTLA-4的细胞表面积累相关。CTLA-4磷酸化诱导CTLA-4与酪氨酸磷酸酶SHP-2结合，但不与磷脂酰肌醇3-激酶结合。相反，LCK诱导的CD 28磷酸化导致磷脂酰肌醇3-激酶的募集，但不是SHP-2。这些发现表明Lck对CD 28和CTLA-4的磷酸化激活了不同的细胞内信号传导途径。CTLA-4与Src激酶和SHP-2的结合导致形成具有调节T细胞活化潜力的CTLA-4复合物。
Cytotoxic T lymphocyte-associated molecule-4 (CTLA-4) is a cell surface receptor expressed on 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 signaling 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.