Small molecule inhibition of Csk alters affinity recognition by T cells

被引：43

作者：

Manz, Boryana N. ^{[1
]}

Tan, Ying Xim ^{[1
]}

Courtney, Adam H. ^{[1
]}

Rutaganira, Florentine ^{[2
,3
]}

Palmer, Ed ^{[4
,5
]}

Shokat, Kevan M. ^{[2
,3
]}

Weiss, Arthur ^{[1
,3
]}

机构：

[1] Univ Calif San Francisco, Dept Med, Div Rheumatol, Rosalind Russell & Ephraim P Engleman Rheumatol R, San Francisco, CA USA

[2] Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94143 USA

[3] Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA USA

[4] Univ Basel, Univ Basel Hosp, Dept Biomed, Basel, Switzerland

[5] Univ Basel, Univ Basel Hosp, Dept Nephrol, Basel, Switzerland

来源：

ELIFE | 2015年 / 4卷

基金：

美国国家科学基金会; 美国国家卫生研究院;

关键词：

TERMINAL SRC KINASE; FAMILY KINASES; THYMIC SELECTION; LIPID RAFTS; ACTIVATION; LCK; TYROSINE; PHOSPHORYLATION; INITIATION; THRESHOLD;

D O I：

10.7554/eLife.08088

中图分类号：

Q [生物科学];

学科分类号：

090105 [作物生产系统与生态工程];

摘要：

The C-terminal Src kinase (Csk), the primary negative regulator of Src-family kinases (SFK), plays a crucial role in controlling basal and inducible receptor signaling. To investigate how Csk activity regulates T cell antigen receptor (TCR) signaling, we utilized a mouse expressing mutated Csk (Csk(AS)) whose catalytic activity is specifically and rapidly inhibited by a small molecule. Inhibition of Csk(AS) during TCR stimulation led to stronger and more prolonged TCR signaling and to increased proliferation. Inhibition of Csk(AS) enhanced activation by weak but strictly cognate agonists. Titration of Csk inhibition revealed that a very small increase in SFK activity was sufficient to potentiate T cell responses to weak agonists. Csk plays an important role, not only in basal signaling, but also in setting the TCR signaling threshold and affinity recognition.

引用

页数：12

共 34 条

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