Department of Pediatrics, Indiana University School of Medicine, Herman B Wells Center for Pediatric Research, Indianapolis, USA.
Blood. 2010 Mar 4;115(9):1785-96. doi: 10.1182/blood-2009-08-237222. Epub 2009 Dec 11.
Rho kinases belong to a family of serine/threonine kinases whose role in recruitment and migration of inflammatory cells is poorly understood. We show that deficiency of ROCK1 results in increased recruitment and migration of macrophages and neutrophils in vitro and in vivo. Enhanced migration resulting from ROCK1 deficiency is observed despite normal expression of ROCK2 and a significant reduction in overall ROCK activity. ROCK1 directly binds PTEN in response to receptor activation and is essential for PTEN phosphorylation and stability. In the absence of ROCK1, PTEN phosphorylation, stability, and its activity are significantly impaired. Consequently, increased activation of downstream targets of PTEN, including PIP3, AKT, GSK-3beta, and cyclin D1, is observed. Our results reveal ROCK1 as a physiologic regulator of PTEN whose function is to repress excessive recruitment of macrophages and neutrophils during acute inflammation.
Rho 激酶属于丝氨酸/苏氨酸激酶家族，其在招募和迁移炎症细胞中的作用尚未完全了解。我们发现 ROCK1 的缺乏导致体外和体内巨噬细胞和中性粒细胞的募集和迁移增加。尽管 ROCK2 的表达正常且整体 ROCK 活性显著降低，但 ROCK1 缺乏导致的迁移增强仍然存在。ROCK1 在受体激活时直接与 PTEN 结合，是 PTEN 磷酸化和稳定性所必需的。在 ROCK1 缺失的情况下，PTEN 磷酸化、稳定性及其活性显著受损。因此，观察到包括 PIP3、AKT、GSK-3β和细胞周期蛋白 D1 在内的 PTEN 下游靶标的激活增加。我们的研究结果揭示了 ROCK1 是 PTEN 的一种生理调节剂，其功能是抑制急性炎症期间巨噬细胞和中性粒细胞的过度募集。
