The hematopoietic isoform of Cas-Hef1-associated signal transducer regulates chemokine-induced inside-out signaling and T cell trafficking
The hematopoietic isoform of Cas-Hef1-associated signal transducer regulates chemokine-induced inside-out signaling and T cell trafficking
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DOI：
10.1016/j.immuni.2006.09.014
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发表时间：
2006-12-01
期刊：
影响因子：
32.4
通讯作者：
Alexandropoulos, Konstantina
中科院分区：
文献类型：
--
作者：
Regelmann, Adam G.;Danzl, Nichole M.;Alexandropoulos, Konstantina
白细胞的迁移和运输受各种趋化因子和黏附分子的动态调节，对免疫系统的正常功能至关重要。我们通过慢病毒介导的RNA干扰(RNAi)，描述了造血细胞中Cas和Hef-1相关的信号转导蛋白(ChAT-H)作为T淋巴细胞迁移的关键调节因子的作用。ChAT-H耗竭细胞的迁移受损与由内向外信号的缺陷相一致，表现为趋化因子诱导的Rap-1 GTP酶激活和整合素介导的黏附减弱。T细胞迁移需要ChAT-H定位于质膜，与其结合伙伴淋巴细胞中Crk相关底物结合，以及ChAT-H介导的CASL丝氨酸-苏氨酸磷酸化。这些结果表明，ChAT-H是作用于RAP1上游的关键信号中间产物，调节趋化因子诱导的黏附和迁移。
Leukocyte migration and trafficking is dynamically regulated by various chemokine and adhesion molecules and is vital to the proper function of the immune system. We describe a role for the Cas and Hef-1-associated signal transducer in hematopoietic cells (Chat-H) as a critical regulator of T lymphocyte migration, by using lentivirus-mediated RNA interference (RNAi). Impaired migration of Chat-H-depleted cells coincided with defective inside-out signaling shown by diminished chemokine-induced activation of the Rap-1 GTPase and integrin-mediated adhesion. Localization of Chat-H to the plasma membrane, association with its binding partner Crk-associated substrate in lymphocytes (CasL), and Chat-H-mediated CasL serine-threonine phosphorylation were required for T cell migration. These results identify Chat-H as a critical signaling intermediate acting upstream of Rap1 to regulate chemokine-induced adhesion and migration.