Vav1 and Rac control chemokine-promoted T lymphocyte adhesion mediated by the integrin α4β1
Vav1 and Rac control chemokine-promoted T lymphocyte adhesion mediated by the integrin α4β1
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DOI：
10.1091/mbc.e04-12-1049
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发表时间：
2005-07-01
影响因子：
3.3
通讯作者：
Teixidó, J
中科院分区：
文献类型：
--
作者：
García-Bernal, D;Wright, N;Teixidó, J
趋化因子CXCL 12促进由整合素α 4 β 1介导的T淋巴细胞粘附。CXCL 12激活GT3 Rac以及Vav 1（一种Rac的鸟嘌呤核苷酸交换因子），同时上调α 4 β 1依赖性粘附。通过转染显性负性Rac或Vav 1形式或通过转染其siRNA抑制CXCL 12促进的Rac和Vav 1活化，显著损害了响应于该趋化因子的T淋巴细胞与α 4 β 1配体附着的增加。重要的是，通过RNA干扰抑制Vav 1表达导致响应于CXCL 12的Rac激活的阻断。流动室中的粘附和使用这些转染子的可溶性结合测定表明，由α 4 β 1介导的初始配体结合和粘附增强依赖于CXCL 12激活的Vav 1和Rac。最后，CXCL 12促进的涉及α 4 β 1介导的粘附的T细胞跨内皮迁移被显性负性Vav 1和Rac的表达显著抑制。这些结果表明，CXCL 12激活Vav 1-Rac信号通路代表了控制α 4 β 1依赖性T淋巴细胞粘附有效上调的重要由内而外事件。
The chemokine CXCL12 promotes T lymphocyte adhesion mediated by the integrin alpha 4 beta 1. CXCL12 activates the GTPase Rac, as well as Vav1, a guanine-nucleotide exchange factor for Rac, concomitant with up-regulation of alpha 4 beta 1-dependent adhesion. Inhibition of CXCL12-promoted Rac and Vav1 activation by transfection of dominant negative Rac or Vav1 forms, or by transfection of their siRNA, remarkably impaired the increase in T lymphocyte attachment to alpha 4 beta 1 ligands in response to this chemokine. Importantly, inhibition of Vav1 expression by RNA interference resulted in a blockade of Rac activation in response to CXCL12. Adhesions in flow chambers and soluble binding assays using these transfectants indicated that initial ligand binding and adhesion strengthening mediated by alpha 4 beta 1 were dependent on Vav1 and Rac activation by CXCL12. Finally, CXCL12-promoted T-cell transendothelial migration involving alpha 4 beta 1-mediated adhesion was notably inhibited by expression of dominant negative Vav1 and Rac. These results indicate that activation of Vav1-Rac signaling pathway by CXCL12 represents an important inside-out event controlling efficient up-regulation of a4p1-dependent T lymphocyte adhesion.