Changchun Teachers College, 677 Changji Northroad, Changchun, China.
J Leukoc Biol. 2013 Apr;93(4):611-22. doi: 10.1189/jlb.1012487. Epub 2013 Jan 16.
The recruitment and migration of neutrophils are critical for innate immunity and acute inflammatory responses. However, the mechanism that regulates the recruitment and migration of neutrophils has not been well characterized. We here reveal a novel function of c-Abl kinase in regulating neutrophil migration. Our results demonstrate that c-Abl kinase is required for neutrophil recruitment in vivo and migration in vitro, and the inhibition of c-Abl kinase activity has a significant impact on neutrophil migratory behavior. Moreover, c-Abl kinase activation depends on β2 integrin engagement, and the activated c-Abl kinase further regulates actin polymerization and membrane protrusion dynamics at the extended leading edges during neutrophil migration. In addition, we identify the Rho GEF Vav1 as a major downstream effector of c-Abl kinase. The C-terminal SH3-SH2-SH3 domain and proline-rich region of Vav1 are required for its interaction with c-Abl kinase, and c-Abl kinase probably regulates the activity of Vav1 by direct phosphorylation at Tyr-267 in the DH domain. Together, these results indicate that c-Abl kinase plays a critical role in β2 integrin-dependent neutrophil migration by regulating Vav1 activity.
中性粒细胞的募集和迁移对于先天免疫和急性炎症反应至关重要。然而，调节中性粒细胞募集和迁移的机制尚未得到很好的描述。我们在这里揭示了 c-Abl 激酶在调节中性粒细胞迁移中的一个新功能。我们的结果表明，c-Abl 激酶在体内中性粒细胞募集和体外迁移中是必需的，抑制 c-Abl 激酶活性对中性粒细胞迁移行为有显著影响。此外，c-Abl 激酶的激活依赖于β2 整合素的结合，并且激活的 c-Abl 激酶进一步调节中性粒细胞迁移过程中延伸前缘处的肌动蛋白聚合和膜突。此外，我们确定 Rho GEF Vav1 是 c-Abl 激酶的主要下游效应物。Vav1 的 C 端 SH3-SH2-SH3 结构域和富含脯氨酸的区域对于其与 c-Abl 激酶的相互作用是必需的，c-Abl 激酶可能通过直接磷酸化 DH 结构域中的 Tyr-267 来调节 Vav1 的活性。总之，这些结果表明 c-Abl 激酶通过调节 Vav1 活性在β2 整合素依赖性中性粒细胞迁移中发挥关键作用。
