Two distinct intracytoplasmic regions of the T-cell adhesion molecule CD28 participate in phosphatidylinositol 3-kinase association
Two distinct intracytoplasmic regions of the T-cell adhesion molecule CD28 participate in phosphatidylinositol 3-kinase association
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DOI：
10.1074/jbc.271.16.9403
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发表时间：
1996-04-19
影响因子：
4.8
通讯作者：
Olive, D
中科院分区：
文献类型：
--
作者：
Pages, F;Ragueneau, M;Olive, D
通过与其配体 CD80/B7-1 和 CD86/B7-2 或 B70 的相互作用，人类 CD28 分子与 CD3-TcR 复合物一起作为 T 细胞的共刺激剂发挥着主要的功能作用。我们和其他人之前报道过磷脂酰肌醇 3-激酶与 CD28 诱导结合。这种关联是由 p85 衔接子亚基的 SH2 结构域与 CD28 中第 173-176 位存在的细胞质 YMNM 共有基序相互作用介导的。通过定点诱变破坏该结合位点，可以消除转染人 CD28 基因的鼠 T 细胞杂交瘤中 CD28 诱导的激活事件。在这里，我们表明 CD28 胞质内结构域的最后 10 个残基（残基 193-202）是其共刺激功能所必需的，这些残基参与白介素 2 分泌、p85 结合和 CD28 相关磷脂酰肌醇 3-激酶活性。相反，CD28/CD80相互作用不受此缺失的影响，其他第二信使的诱导也不受此影响，例如细胞内钙的增加和CD28特异性底物的酪氨酸磷酸化。此外，我们还证明，在这些残基中，位置200的酪氨酸参与p85结合，可能与残基190和194之间存在的短的富含脯氨酸的基序一起（PYAPP）。
Through the interaction with its ligands, CD80/B7-1 and CD86/B7-2 or B70, the human CD28 molecule plays a major functional role as a costimulator of T cells along with the CD3-TcR complex, We and others have previously reported that phosphatidylinositol 3-kinase inducibly associates with CD28. This association is mediated by the SH2 domains of the p85 adaptor subunit interacting with a cytoplasmic YMNM consensus motif present in CD28 at position 173-176. Disruption of this binding site by site-directed mutagenesis abolishes CD28-induced activation events in a murine T-cell hybridoma transfected with human CD28 gene.Here we show that the last 10 residues of the intracytoplasmic domain of CD28 (residues 193-202) are required for its costimulatory function, These residues are involved in interleukin-2 secretion, p85 binding, and CD28-associated phosphatidylinositol 3-kinase activity. In contrast, the CD28/CD80 interaction is unaffected by this deletion, as is the induction of other second messengers such as the rise in intracellular calcium and tyrosine phosphorylation of CD28-specific substrates, Furthermore, we also demonstrate that, within these residues, the tyrosine at position 200 is involved in p85 binding, probably together with the short proline-rich motif present between residues 190 and 194 (PYAPP).