RIAM links the ADAP/SKAP-55 signaling module to Rap1, facilitating T-cell-receptor-mediated integrin activation
RIAM links the ADAP/SKAP-55 signaling module to Rap1, facilitating T-cell-receptor-mediated integrin activation
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DOI：
10.1128/mcb.02011-06
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发表时间：
2007-06-01
影响因子：
5.3
通讯作者：
Koretzky, Gary
中科院分区：
文献类型：
--
作者：
Menasche, Gael;Kliche, Stefanie;Koretzky, Gary
T细胞受体（TCR）信号传导的一个结果是整联蛋白对其配体的亲和力和亲合力增加。这是通过一个被称为由内而外信号传导的过程发生的，该过程已被证明需要几种分子组分，包括衔接蛋白ADAP（粘附和脱颗粒促进衔接蛋白）和SKAP-55（55 kDa src激酶相关磷蛋白）以及小GTdR Rap 1。在此，我们提供了证据，ADAP和SKAP-55连接到RLAM，最近描述的衔接蛋白，选择性地结合到活性Rap 1。我们确定RIAM是连接ADAP/SKAP-55模块与小GTdR Rap 1，促进TCR介导的整合素活化的关键组分。我们发现RIAM在异源转染系统和原代T细胞中与SKAP-55组成性相互作用，并绘制了这种相互作用所必需的区域。此外，我们发现SKAP-55/RIAM复合物对于TCR介导的粘附和T细胞与抗原呈递细胞之间的有效缀合物形成都是必需的。机制研究表明，ADAP/SKAP-55模块在TCR活化后将RLAM和Rap 1重新定位于质膜，以促进整合素活化。这些结果首次描述了ADAP/SKAP-55和Rap 1/RLAM复合物之间的联系，并为TCR介导的整合素激活提供了潜在的新机制。
One outcome of T-cell receptor (TCR) signaling is increased affinity and avidity of integrins for their ligands. This occurs through a process known as inside-out signaling, which has been shown to require several molecular components including the adapter proteins ADAP (adhesion and degranulation-promoting adapter protein) and SKAP-55 (55-kDa src kinase-associated phosphoprotein) and the small GTPase Rap1. Herein, we provide evidence linking ADAP and SKAP-55 to RLAM, a recently described adapter protein that binds selectively to active Rap1. We identified RIAM as a key component linking the ADAP/SKAP-55 module to the small GTPase Rap1, facilitating TCR-mediated integrin activation. We show that RIAM constitutively interacts with SKAP-55 in both a heterologous transfection system and primary T cells and map the region essential for this interaction. Additionally, we find that the SKAP-55/RIAM complex is essential both for TCR-mediated adhesion and for efficient conjugate formation between T cells and antigen-presenting cells. Mechanistic studies revealed that the ADAP/SKAP-55 module relocalized RLAM and Rap1 to the plasma membrane following TCR activation to facilitate integrin activation. These results describe for the first time a link between ADAP/SKAP-55 and the Rap1/RLAM complex and provide a potential new mechanism for TCR-mediated integrin activation.