Role of HS1 in Actin Regulation During T Cell Activation

描述（由申请人提供）：旨在理解T细胞激活过程中利用的信号转导机制的努力为开发药物或基因操纵T细胞的策略提供了基础。肌动蛋白细胞骨架在T细胞活化和功能中起关键作用，被认为在免疫突触（is）组织淋巴细胞信号复合物。该领域的一个主要研究焦点是Wiskott- Aldrich综合征蛋白（WASp），它在T细胞活化中起着明确的作用。然而，最近的数据表明，在IS上形成F-actin可能不需要WASp，因此必须有其他机制促成这一现象。该应用程序的重点是白细胞特异性的同源物，HS1，一种结合肌动蛋白和Arp2/3复合物的多域信号分子。虽然HS1在体外调节f -肌动蛋白聚合，但尚未确定HS1在控制淋巴细胞肌动蛋白重组中的功能作用。我们的初步数据表明，在T细胞激活过程中，HS1是F-actin在is积累所必需的。因此，我们假设HS1与已知的肌动蛋白调控蛋白（包括Vav1和Itk）合作，在T细胞活化过程中重组肌动蛋白细胞骨架。

DESCRIPTION (provided by applicant): Efforts aimed at understanding the signal transduction mechanisms utilized during T cell activation provide a foundation for developing strategies to pharmacologically or genetically manipulate T cells. The actin cytoskeleton plays a key role in T cell activation and function and is thought to organize lymphocyte signaling complexes at the immunological synapse (IS). A major focus of research in this area has been the Wiskott- Aldrich Syndrome protein (WASp), which plays a clear role in T cell activation. However, recent data suggest that WASp may not be required for the formation of F-actin at the IS, so other mechanisms must contribute to this phenomenon. This application focuses on the leukocyte-specific homologue of Cortactin, HS1, a multi-domain signaling molecule that binds actin and the Arp2/3 Complex. Although HS1 regulates F-actin polymerization in vitro, no functional role for HS1 in controlling actin reorganization in lymphocytes has been established. Our preliminary data demonstrate that HS1 is required for the accumulation of F-actin at the IS during T cell activation. Therefore, we hypothesize that HS1 cooperates with the known actin- regulatory proteins, including Vav1 and Itk, to reorganize the actin cytoskeleton during T cell activation.