Binding of the cytoplasmic domain of CD28 to the plasma membrane inhibits Lck recruitment and signaling.
Binding of the cytoplasmic domain of CD28 to the plasma membrane inhibits Lck recruitment and signaling.
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DOI：
10.1126/scisignal.aaf0626
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发表时间：
2016-07-26
影响因子：
7.3
通讯作者：
Wucherpfennig KW
中科院分区：
文献类型：
--
作者：
Dobbins J;Gagnon E;Godec J;Pyrdol J;Vignali DA;Sharpe AH;Wucherpfennig KW
T细胞共刺激受体CD28对于naïve T细胞的完全激活以及Foxp3+调节性T （Treg）细胞的发育和维持是必需的。我们发现，在静止细胞中，CD28的细胞质结构域与质膜结合，并且与CD28结合的配体导致其释放。CD28细胞质结构域的膜结合需要两簇碱性氨基酸残基，它们与带负电荷的质膜内小叶相互作用。这些相同的基本残基簇也作为Lck的相互作用位点，Lck是一种Src家族激酶，对CD28功能至关重要。通过Lck介导的CD28 Tyr207磷酸化以及随后Lck的Src同源性2 （SH2）结构域与磷酸化的酪氨酸结合，该信号复合物进一步稳定。CD28细胞质结构域的基本簇突变减少了蛋白激酶Cθ (PKCθ)对CD28- lck复合物的募集，PKCθ是CD28信号通路中的关键效应激酶。因此，基本簇或Tyr207的突变都会损害小鼠的CD28功能，FoxP3+ Treg细胞的胸腺分化减少表明了这一点。在这些结果的基础上，我们提出了一个以前未描述的CD28信号传导的启动模型。
The T cell costimulatory receptor CD28 is required for the full activation of naïve T cells and for the development and maintenance of Foxp3+ regulatory T (Treg) cells. We showed that the cytoplasmic domain of CD28 was bound to the plasma membrane in resting cells and that ligand binding to CD28 resulted in its release. Membrane binding by the CD28 cytoplasmic domain required two clusters of basic amino acid residues, which interacted with the negatively charged inner leaflet of the plasma membrane. These same clusters of basic residues also served as interaction sites for Lck, a Src family kinase critical for CD28 function. This signaling complex was further stabilized by the Lck-mediated phosphorylation of CD28 Tyr207 and the subsequent binding of the Src homology 2 (SH2) domain of Lck to this phosphorylated tyrosine. Mutation of the basic clusters in the CD28 cytoplasmic domain reduced the recruitment to the CD28-Lck complex of protein kinase Cθ (PKCθ), which serves as a key effector kinase in the CD28 signaling pathway. Consequently, mutation of either a basic cluster or Tyr207 impaired CD28 function in mice as shown by the reduced thymic differentiation of FoxP3+ Treg cells. On the basis of these results, we propose a previously un-described model for the initiation of CD28 signaling.
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DOI：
10.1084/jem.20052230
发表时间：
2006-09-04
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Friend LD;Shah DD;Deppong C;Lin J;Bricker TL;Juehne TI;Rose CM;Green JM
通讯作者：
Green JM
影响因子：
11.4
作者：
BIFFEN, M;MCMICHAELPHILLIPS, D;ALEXANDER, D
通讯作者：
ALEXANDER, D
DOI：
10.1084/jem.190.3.375
发表时间：
1999-08-02
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Holdorf AD;Green JM;Levin SD;Denny MF;Straus DB;Link V;Changelian PS;Allen PM;Shaw AS
通讯作者：
Shaw AS
影响因子：
30.5
作者：
Irles, C;Symons, A;Acuto, O
通讯作者：
Acuto, O
影响因子：
30.5
作者：
Kong, Kok-Fai;Yokosuka, Tadashi;Canonigo-Balancio, Ann J.;Isakov, Noah;Saito, Takashi;Altman, Amnon
通讯作者：
Altman, Amnon