Haematopoietic cell-specific CDM family protein DOCK2 is essential for lymphocyte migration
Haematopoietic cell-specific CDM family protein DOCK2 is essential for lymphocyte migration
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DOI：
10.1038/35090591
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发表时间：
2001-08-23
期刊：
影响因子：
64.8
通讯作者：
Sasazuki, T
中科院分区：
文献类型：
--
作者：
Fukui, Y;Hashimoto, O;Sasazuki, T
细胞迁移是涉及膜极化和细胞骨架动力学的基本生物学过程（1），这两者都由Rho家族GTP酶调节（2-5）。在这些分子中，Rac对于产生富含肌动蛋白的片状伪足突起至关重要，这是运动驱动力的主要部分（3，6）。CDM家族蛋白质，秀丽隐杆线虫CED-5、人DOCK 180和黑腹果蝇成肌细胞城（MBC），涉及通过在Rac上游起作用来介导膜延伸（7-12）。尽管遗传分析表明CED-5和成肌细胞城对于特定类型细胞的迁移至关重要（8，9，12），但哺乳动物中CDM家族蛋白的生理相关性仍然未知。在这里，我们表明DOCK 2，一种造血细胞特异性CDM家族蛋白（13），是淋巴细胞趋化性不可或缺的。DOCK 2缺陷小鼠（DOCK 2（-/-））表现出T和B淋巴细胞对趋化因子的迁移缺陷，但单核细胞没有迁移缺陷，导致几种异常，包括T淋巴细胞减少、淋巴滤泡萎缩和边缘区B细胞丢失。在DOCK 2（-/-）淋巴细胞中，趋化因子诱导的Rac活化和肌动蛋白聚合几乎完全消除。因此，在淋巴细胞迁移中，DOCK 2作为中央调节因子发挥作用，通过Rac激活介导细胞骨架重组。
Cell migration is a fundamental biological process involving membrane polarization and cytoskeletal dynamics(1), both of which are regulated by Rho family GTPases(2-5). Among these molecules, Rac is crucial for generating the actin-rich lamellipodial protrusion, a principal part of the driving force for movement(3,6). The CDM family proteins, Caenorhabditis elegans CED-5, human DOCK180 and Drosophila melanogaster Myoblast City (MBC), are implicated to mediate membrane extension by functioning upstream of Rac(7-12). Although genetic analysis has shown that CED-5 and Myoblast City are crucial for migration of particular types of cells(8,9,12), physiological relevance of the CDM family proteins in mammals remains unknown. Here we show that DOCK2, a haematopoietic cell-specific CDM family protein(13), is indispensable for lymphocyte chemotaxis. DOCK2-dercient mice (DOCK2(-/-)) exhibited migration defects of T and B lymphocytes, but not of monocytes, in response to chemokines, resulting in several abnormalities including T lymphocytopenia, atrophy of lymphoid follicles and loss of marginal-zone B cells. In DOCK2(-/-) lymphocytes, chemokine-induced Rac activation and actin polymerization were almost totally abolished. Thus, in lymphocyte migration DOCK2 functions as a central regulator that mediates cytoskeletal reorganization through Rac activation.