Sanui Terukazu, Inayoshi Ayumi, Noda Mayuko, Iwata Eiko, Stein Jens V, Sasazuki Takehiko, Fukui Yoshinori
Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Blood. 2003 Oct 15;102(8):2948-50. doi: 10.1182/blood-2003-01-0173. Epub 2003 Jun 26.
Although the migratory property of lymphocytes is critical for protective immunity, tissue infiltration of lymphocytes sometimes causes harmful immune responses. DOCK2 plays a critical role in lymphocyte migration by regulating actin cytoskeleton through Rac activation, yet the mechanism by which DOCK2 activates Rac remains unknown. We found that DOCK2 associates with engulfment and cell motility (ELMO1) through its Src-homology 3 (SH3) domain. When DOCK2 was expressed in T-hybridoma cells lacking endogenous expression of DOCK2, Rac activation and actin polymerization were induced. However, such responses were not elicited by the DOCK2 mutant lacking the region required for ELMO1 binding. On the other hand, we found that the expression of ELMO1 induces Rac activation in the plasmacytoma cells expressing DOCK2 but not ELMO1. These results indicate that the association of DOCK2 with ELMO1 is critical for DOCK2-mediated Rac activation, thereby suggesting that their association might be a therapeutic target for immunologic disorders caused by lymphocyte infiltration.
尽管淋巴细胞的迁移特性对保护性免疫至关重要，但淋巴细胞的组织浸润有时会引发有害的免疫反应。DOCK2通过激活Rac调节肌动蛋白细胞骨架，在淋巴细胞迁移中起关键作用，然而DOCK2激活Rac的机制尚不清楚。我们发现DOCK2通过其Src同源3（SH3）结构域与吞噬和细胞运动（ELMO1）相关联。当在缺乏内源性DOCK2表达的T杂交瘤细胞中表达DOCK2时，会诱导Rac激活和肌动蛋白聚合。然而，缺乏ELMO1结合所需区域的DOCK2突变体不会引发这种反应。另一方面，我们发现ELMO1的表达在表达DOCK2但不表达ELMO1的浆细胞瘤细胞中诱导Rac激活。这些结果表明DOCK2与ELMO1的关联对于DOCK2介导的Rac激活至关重要，从而表明它们的关联可能是淋巴细胞浸润引起的免疫紊乱的治疗靶点。
