清脆的
调节器
细胞生物学
负调节器
生物
PI3K/AKT/mTOR通路
细胞粘附
粘附
效应器
化学
遗传学
信号转导
基因
细胞
有机化学
作者
K. Johansen,Dominic P. Golec,Bruce Huang,Chung Park,Julie H Thomsen,Silvia Preite,Jennifer L. Cannons,Fabien Garçon,Edward C. Schrom,Christina J. F. Courrèges,Tibor Z. Veres,James Harrison,Meritxell Nus,James D. Phelan,Wolfgang Bergmeier,John H. Kehrl,Klaus Okkenhaug,Pamela L. Schwartzberg
出处
期刊:Science Signaling
[American Association for the Advancement of Science (AAAS)]
日期:2022-07-19
卷期号:15 (743)
被引量:16
标识
DOI:10.1126/scisignal.abl9169
摘要
The integrin lymphocyte function–associated antigen 1 (LFA-1) helps to coordinate the migration, adhesion, and activation of T cells through interactions with intercellular adhesion molecule 1 (ICAM-1) and ICAM-2. LFA-1 is activated during the engagement of chemokine receptors and the T cell receptor (TCR) through inside-out signaling, a process that is partially mediated by phosphoinositide 3-kinase (PI3K) and its product phosphatidylinositol 3,4,5-trisphosphate (PIP 3 ). To evaluate potential roles of PI3K in LFA-1 activation, we designed a library of CRISPR/single guide RNAs targeting known and potential PIP 3 -binding proteins and screened for effects on the ability of primary mouse T cells to bind to ICAM-1. We identified multiple proteins that regulated the binding of LFA-1 to ICAM-1, including the Rap1 and Ras GTPase-activating protein RASA3. We found that RASA3 suppressed LFA-1 activation in T cells, that its expression was rapidly reduced upon T cell activation, and that its activity was inhibited by PI3K. Loss of RASA3 in T cells led to increased Rap1 activation, defective lymph node entry and egress, and impaired responses to T-dependent immunization in mice. Our results reveal a critical role for RASA3 in T cell migration, homeostasis, and function.
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