Lck, Membrane Microdomains, and TCR Triggering Machinery: Defining the New Rules of Engagement.
Lck, Membrane Microdomains, and TCR Triggering Machinery: Defining the New Rules of Engagement.
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DOI：
10.3389/fimmu.2012.00155
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发表时间：
2012
影响因子：
7.3
通讯作者：
Manning J
中科院分区：
文献类型：
--
作者：
Filipp D;Ballek O;Manning J
尽管对T细胞受体(TCR)信号转导机制有了全面的了解，但TCR参与后信号分子的区间化、瞬时相互作用和膜结构重排的调控机制仍然是一个突出的问题。最近的数据表明，TCR的触发在很大程度上依赖于集中在特定类型膜微域的T细胞中的预先激活的LCK池，这说明了我们知识中的这些差距。我们目前的模型假设，在静息T细胞中，TCR触发机制的所有关键组件，包括TCR/CD3、Lck、Fyn、CD45、PAG和LAT，都与不同类型的脂基微域有关，这些微域代表了膜限制的最小结构和功能单元，可以负向控制酶的活性和启动TCR信号所需的底物的可用性。此外，基于微域的分离在空间上限制了TCR触发机制组件在TCR信号开始之前的相互作用，并允许它们在TCR参与后通过它们的结合过程进行快速通信和信号放大。因此，微域介导的区域化是静息T细胞的一种基本的膜组织原则。将这些信号的结构和功能方面整合到TCR触发的统一模型中，将需要对膜生物学、新的跨学科方法和特定试剂的生成有更深入的了解。我们认为，TCR信号的完全集成模型必须基于膜结构网络，膜结构网络为控制TCR触发的调控过程提供了合适的环境。
In spite of a comprehensive understanding of the schematics of T cell receptor (TCR) signaling, the mechanisms regulating compartmentalization of signaling molecules, their transient interactions, and rearrangement of membrane structures initiated upon TCR engagement remain an outstanding problem. These gaps in our knowledge are exemplified by recent data demonstrating that TCR triggering is largely dependent on a preactivated pool of Lck concentrated in T cells in a specific type of membrane microdomains. Our current model posits that in resting T cells all critical components of TCR triggering machinery including TCR/CD3, Lck, Fyn, CD45, PAG, and LAT are associated with distinct types of lipid-based microdomains which represent the smallest structural and functional units of membrane confinement able to negatively control enzymatic activities and substrate availability that is required for the initiation of TCR signaling. In addition, the microdomains based segregation spatially limits the interaction of components of TCR triggering machinery prior to the onset of TCR signaling and allows their rapid communication and signal amplification after TCR engagement, via the process of their coalescence. Microdomains mediated compartmentalization thus represents an essential membrane organizing principle in resting T cells. The integration of these structural and functional aspects of signaling into a unified model of TCR triggering will require a deeper understanding of membrane biology, novel interdisciplinary approaches and the generation of specific reagents. We believe that the fully integrated model of TCR signaling must be based on membrane structural network which provides a proper environment for regulatory processes controlling TCR triggering.
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影响因子：
11.4
作者：
BIFFEN, M;MCMICHAELPHILLIPS, D;ALEXANDER, D
通讯作者：
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影响因子：
15.3
作者：
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3.9
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影响因子：
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Sefton, BM
影响因子：
4.8
作者：
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通讯作者：
Rodgers, William