Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093-0380, USA.
Mol Biol Cell. 2011 Jul 1;22(13):2198-211. doi: 10.1091/mbc.E10-12-0937. Epub 2011 May 5.
We identify a new pathway that is required for proper pseudopod formation. We show that Roco2, a leucine-rich repeat kinase 2 (LRRK2)-related Roco kinase, is activated in response to chemoattractant stimulation and helps mediate cell polarization and chemotaxis by regulating cortical F-actin polymerization and pseudopod extension in a pathway that requires Rab1A. We found that Roco2 binds the small GTPase Rab1A as well as the F-actin cross-linking protein filamin (actin-binding protein 120, abp120) in vivo. We show that active Rab1A (Rab1A-GTP) is required for and regulates Roco2 kinase activity in vivo and that filamin lies downstream from Roco2 and controls pseudopod extension during chemotaxis and random cell motility. Therefore our study uncovered a new signaling pathway that involves Rab1A and controls the actin cytoskeleton and pseudopod extension, and thereby, cell polarity and motility. These findings also may have implications in the regulation of other Roco kinases, including possibly LRRK2, in metazoans.
我们发现了一个新的通路,该通路对于伪足的正常形成是必需的。我们发现富含亮氨酸重复激酶 2(LRRK2)相关的 Roco 激酶 Roco2 会被趋化因子刺激激活,通过调节皮层肌动蛋白聚合和伪足延伸,在依赖 Rab1A 的途径中帮助调节细胞极化和趋化性。我们发现 Roco2 体内可以结合小 GTP 酶 Rab1A 以及肌动蛋白交联蛋白细丝蛋白(肌动蛋白结合蛋白 120,abp120)。我们表明,活性 Rab1A(Rab1A-GTP)在体内是 Roco2 激酶活性所必需的,并且调控其活性,而细丝蛋白位于 Roco2 的下游,并在趋化和随机细胞运动过程中控制伪足延伸。因此,我们的研究揭示了一个新的信号通路,该通路涉及 Rab1A 并调控肌动蛋白细胞骨架和伪足延伸,从而调控细胞极性和运动性。这些发现可能对其他 Roco 激酶(包括可能的 LRRK2)在后生动物中的调控具有意义。