DOCK2 regulates chemokine-triggered lateral lymphocyte motility but not transendothelial migration
DOCK2 regulates chemokine-triggered lateral lymphocyte motility but not transendothelial migration
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DOI：
10.1182/blood-2006-04-017608
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发表时间：
2006-10-01
期刊：
影响因子：
20.3
通讯作者：
Alon, Ronen
中科院分区：
文献类型：
--
作者：
Shulman, Ziv;Pasvolsky, Ronit;Alon, Ronen
Rac GTP酶是白细胞运动的关键调节因子。在淋巴细胞中，趋化因子介导的Rac活化依赖于CDM衔接子DOCK 2。目前的研究致力于DOCK 2在趋化因子触发的淋巴细胞粘附和运动中的作用。趋化因子触发的LFA-1和VLA-4整联蛋白的快速活化在各种剪切流条件下正常地发生在DOCK 2（-/-）T淋巴细胞中。因此，DOCK 2（-/-）T细胞通常在TNF α激活的内皮细胞上响应整合素刺激性趋化因子信号而被阻滞，并且它们对脱离的抵抗力与野生型（wt）T淋巴细胞相似。然而，DOCK 2（-/-）T淋巴细胞表现出减少微绒毛塌陷和lannellipodium延长响应趋化因子信号，排除了这些事件中的作用，整合素介导的粘附加强。引人注目的是，被捕的DOCK 2（-/-）淋巴细胞通过CCL 21呈递内皮屏障的迁移效率和速率与野生型淋巴细胞相似，但与野生型淋巴细胞不同，不能从基底内皮侧的迁移位点迁移。DOCK 2（-/-）淋巴细胞也不能在与趋化因子共固定的多个整合素配体上横向迁移。这是T淋巴细胞使用2种不同的趋化因子触发的肌动蛋白重塑程序的第一个指示：第一个是DOCK 2依赖性的，沿着顶端和基底内皮表面侧向移动;第二个是DOCK 2独立的，穿过承载趋化因子的内皮屏障。
Rac GTPases are key regulators of leukocyte motility. In lymphocytes, chemokine-mediated Rac activation depends on the CDM adaptor DOCK2. The present studies addressed the role of DOCK2 in chemokine-triggered lymphocyte adhesion and motility. Rapid chemokine-triggered activation of both LFA-1 and VLA-4 integrins took place normally in DOCK2(-/-) T lymphocytes under various shear flow conditions. Consequently, DOCK2(-/-) T cells arrested normally on TNF alpha-activated endothelial cells in response to integrin stimulatory chemokine signals, and their resistance to detachment was similar to that of wild-type (wt) T lymphocytes. Nevertheless, DOCK2(-/-) T lymphocytes exhibited reduced microvillar collapse and lannellipodium extension in response to chemokine signals, ruling out a role for these events in integrin-mediated adhesion strengthening. Strikingly, arrested DOCK2(-/-) lymphocytes transmigrated through a CCL21-presenting endothelial barrier with similar efficiency and rate as wt lymphocytes but, unlike wt lymphocytes, could not loconnote away from the transmigration site of the basal endothelial side. DOCK2(-/-) lymphocytes also failed to laterally migrate over multiple integrin ligands coimmobilized with chemokines. This is a first indication that T lymphocytes use 2 different chemokine-triggered actin remodeling programs: the first, DOCK2 dependent, to locomote laterally along apical and basal endothelial surfaces; the second, DOCK2 independent, to cross through a chemokine-bearing endothelial barrier.