Role of HS1 in Actin Regulation During T Cell Activation

描述（由申请人提供）：旨在理解T细胞活化过程中使用的信号转导机制的努力为开发T细胞增殖或遗传操纵的策略提供了基础。肌动蛋白细胞骨架在T细胞活化和功能中起关键作用，并且被认为在免疫突触（IS）处组织淋巴细胞信号传导复合物。该领域的主要研究焦点是Wiskott-Aldrich综合征蛋白（WASp），它在T细胞活化中起着明显的作用。然而，最近的数据表明，WASp可能不需要在IS形成F-肌动蛋白，所以其他机制必须有助于这种现象。本申请的重点是白细胞特异性的同源Corpyn，HS 1，多域信号分子，结合肌动蛋白和Arp 2/3复合物。虽然HS 1调节F-肌动蛋白聚合在体外，没有功能的作用HS 1控制肌动蛋白重组淋巴细胞已建立。我们的初步数据表明，HS 1所需的F-肌动蛋白的积累在IS在T细胞活化过程中。因此，我们假设HS 1与已知的肌动蛋白调节蛋白，包括Vav 1和Itk，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.