A genetically selective inhibitor demonstrates a function for the kinase Zap70 in regulatory T cells independent of its catalytic activity.
A genetically selective inhibitor demonstrates a function for the kinase Zap70 in regulatory T cells independent of its catalytic activity.
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作者：
为了研究70 kDa激酶zeta相关蛋白（ZAP-70）在T细胞中的作用，我们培养了表达ZAP-70突变体的小鼠，其催化活性可以被一种小分子抑制剂选择性阻断。传统的naïve、效应T细胞和记忆T细胞依赖于ZAP-70激酶活性来激活，这表明ZAP-70在tcr诱导的信号中具有非冗余作用。相比之下，ZAP-70的催化活性并不需要激活GTPase Rap1和促进整合素粘附的内向外信号。这种不依赖于ZAP-70激酶的途径足以调节T （TREG）细胞抑制活性，而这种抑制活性不受ZAP-70催化抑制的干扰。我们的结果表明ZAP-70是一个有吸引力的治疗靶点。
To investigate the role of the kinase zeta-associated protein of 70 kDa (ZAP-70) in T cells, we generated mice expressing a ZAP-70 mutant whose catalytic activity can be selectively blocked by a small molecule inhibitor. Conventional naïve, effector and memory T cells were dependent on ZAP-70 kinase activity for their activation, demonstrating a non-redundant role for ZAP-70 in TCR-induced signals. In contrast, ZAP-70 catalytic activity was not required for activation of the GTPase Rap1 and inside-out signals that promote integrin adhesion. This ZAP-70 kinase-independent pathway is sufficient for regulatory T (TREG) cell suppressive activity, which was unperturbed by ZAP-70 catalytic inhibition. Our results implicate ZAP-70 as an attractive therapeutic target.
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DOI：
10.4049/jimmunol.0803827
发表时间：
2009-03-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Tran DQ;Glass DD;Uzel G;Darnell DA;Spalding C;Holland SM;Shevach EM
通讯作者：
Shevach EM
ZAP-70 的亚等位基因揭示了自身免疫性疾病与自身免疫反应性的不同胸腺阈值。
DOI：
10.1084/jem.20082902
发表时间：
2009-10-26
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Hsu LY;Tan YX;Xiao Z;Malissen M;Weiss A
通讯作者：
Weiss A
影响因子：
4.8
作者：
Gelkop, S;Isakov, N
通讯作者：
Isakov, N
影响因子：
64.8
作者：
NEGISHI, I;MOTOYAMA, N;LOH, DY
通讯作者：
LOH, DY
影响因子：
4.4
作者：
Tanaka, Satoshi;Maeda, Shinji;Sakaguchi, Shimon
通讯作者：
Sakaguchi, Shimon