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Role of the CDM family protein DOCK2 in lymphocyte functions

CDM家族蛋白DOCK2在淋巴细胞功能中的作用

基本信息

批准号：
14370113
负责人：
FUKUI Yoshinori
金额：
$ 8.77万
依托单位：
Kyushu University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370113/
关键词：
actin cytoskeleton immunological synapse Rac immune regulation サイトカインシグナル伝達

项目摘要

Remodeling of the actin cytoskeleton is a fundamental biological response that regulates various cellular functions in the immune system. For example, it is currently considered that phagocytosis of foreign antigens or apoptotic cells by macrophages, migration of lymphoid and myeloid cells, and immunological synapse formation in T cells are critically regulated by remodeling of the actin cytoskeleton, yet the molecular mechanism involved in this process is poorly understood.The CDM family proteins are the molecules conserved Caenorhabditis elegans, Drosophila melanogaster and mammals, and regulate remodeling of the actin cytoskeleton by functioning upstream of Rac. -We have identified DOCK2, a new member of the CDM family proteins, that is predominantly expressed in lymphocytes. By generating DOCK2-deficient mice, we demonstrated that DOCK2 functions downstream of chemokine receptors and T cell antigen receptor, and plays an important role in lymphocyte migration and immunological synapse formation through activation of Rac. In addition, we found that interaction of DOCK2 with ELMO1 is critical for Rac activation and cytoskeletal reorganization. Therefore, our findings suggest that DOCK2-ELMO1 interaction would b,e a novel molecular target for immune-related diseases caused by infiltration and activation of T cells.

肌动蛋白细胞骨架的重塑是调节免疫系统中各种细胞功能的基本生物反应。例如，目前认为巨噬细胞对外来抗原或凋亡细胞的吞噬作用、淋巴样和骨髓样细胞的迁移以及T细胞中免疫突触的形成受到肌动蛋白细胞骨架重塑的关键调节，但对该过程中涉及的分子机制知之甚少。CDM家族蛋白是秀丽隐杆线虫、黑腹果蝇和哺乳动物中保守的分子，并通过Rac上游的功能调节肌动蛋白细胞骨架的重塑。我们已经鉴定了DOCK 2，这是CDM家族蛋白的新成员，主要在淋巴细胞中表达。通过产生DOCK 2缺陷小鼠，我们证明了DOCK 2在趋化因子受体和T细胞抗原受体的下游起作用，并且通过激活Rac在淋巴细胞迁移和免疫突触形成中起重要作用。此外，我们发现DOCK 2与ELMO 1的相互作用对于Rac激活和细胞骨架重组至关重要。因此，我们的研究结果表明，DOCK 2-ELMO 1相互作用将B，e一个新的分子靶点，免疫相关疾病所引起的浸润和活化的T细胞。