αPIX RhoGEF Supports Positive Selection by Restraining Migration and Promoting Arrest of Thymocytes
αPIX RhoGEF Supports Positive Selection by Restraining Migration and Promoting Arrest of Thymocytes
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DOI：
10.4049/jimmunol.1302585
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发表时间：
2014-04-01
影响因子：
4.4
通讯作者：
Fischer, Klaus-Dieter
中科院分区：
文献类型：
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作者：
Korthals, Mark;Schilling, Kerstin;Fischer, Klaus-Dieter
胸腺细胞通过迁移通过胸腺的特定区域并与其他细胞相互作用以接收必要的发育信号而在一系列阶段中成熟;然而，对管理这种迁移的分子机制知之甚少。我们报告说，小鼠胸腺细胞与α-PAK（p21激活激酶）相互作用交换因子（PIX; Arhgef 6），Rho GTPases的激活剂，敲除突变，表现出极大的增加运动和改变ICAM-1的二维迁移的形态。α PIX也是胸腺细胞的有效正选择而非负选择所必需的。TCR信号在α PIX（-）胸腺细胞中是正常的，表明α PIX对阳性选择的影响在很大程度上独立于TCR信号。α Pix（-）胸腺细胞在胸腺皮质迁移期间也较少停顿，与ICAM-1包被的珠相互作用较少，并且可以克服TCR停止信号，这与有缺陷的扫描行为一致。这些结果鉴定了α PIX作为胸腺细胞迁移和随后的与正选择相关的停滞的调节剂。
Thymocytes mature in a series of stages by migrating through specific areas of the thymus and interacting with other cells to receive the necessary developmental signals; however, little is known about the molecular mechanisms governing this migration. We report that murine thymocytes with a knockout mutation in alpha-PAK (p21-activated kinase)-interacting exchange factor (PIX; Arhgef6), an activator of Rho GTPases, showed greatly increased motility and altered morphology in two-dimensional migration on ICAM-1. alpha PIX was also required for efficient positive selection, but not negative selection, of thymocytes. TCR signaling was normal in alpha Pix(-) thymocytes, indicating that the effects of alpha PIX on positive selection are largely independent of TCR signaling. alpha Pix(-) thymocytes also paused less during migration in the thymic cortex, interacted less with ICAM-1 coated beads, and could overcome TCR stop signals, consistent with defective scanning behavior. These results identify alpha PIX as a regulator of thymocyte migration and subsequent arrest that is linked to positive selection.