Takenawa T, Miki H
Department of Biochemistry, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
J Cell Sci. 2001 May;114(Pt 10):1801-9. doi: 10.1242/jcs.114.10.1801.
Reorganization of cortical actin filaments plays critical roles in cell movement and pattern formation. Recently, the WASP and WAVE family proteins WASP and N-WASP, and WAVE1, WAVE2 and WAVE3 have been shown to regulate cortical actin filament reorganization in response to extracellular stimuli. These proteins each have a verprolin-homology (V) domain, cofilin-homology (C) domain and an acidic (A) region at the C-terminus, through which they activate the Arp2/3 complex, leading to rapid actin polymerization. N-WASP is usually present as an inactive form in which the VCA region is masked. Cooperative binding of Cdc42 and phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P(2)) exposes the VCA region, activating N-WASP. In addition to this activation mechanism, WISH also activates N-WASP independently of Cdc42 and PtdIns(4,5)P(2), by binding to the proline-rich region of N-WASP. N-WASP activation induces formation of filopodia in vivo. In contrast, the ubiquitously expressed form of WAVE2 is activated downstream of Rac, leading to formation of lamellipodia. In this case, IRSp53 transmits a signal from Rac to WAVE2 through formation of a ternary Rac-IRSp53-WAVE2 complex. Thus, N-WASP, which is activated downstream of Cdc42 or independently by WISH, induces formation of filopodia and WAVE2, which is activated via IRSp53 downstream of Rac, induces formation of lamellipodia.
皮层肌动蛋白丝的重组在细胞运动和模式形成中起着关键作用。最近，WASP和WAVE家族蛋白WASP、N-WASP以及WAVE1、WAVE2和WAVE3已被证明可响应细胞外刺激调节皮层肌动蛋白丝的重组。这些蛋白在C端均具有一个维普洛林同源（V）结构域、丝切蛋白同源（C）结构域和一个酸性（A）区域，通过这些区域它们激活Arp2/3复合物，导致肌动蛋白快速聚合。N-WASP通常以无活性形式存在，其中VCA区域被掩盖。Cdc42和磷脂酰肌醇4,5-二磷酸（PtdIns(4,5)P(2)）的协同结合会暴露VCA区域，从而激活N-WASP。除了这种激活机制外，WISH还通过与N-WASP富含脯氨酸的区域结合，独立于Cdc42和PtdIns(4,5)P(2)激活N-WASP。N-WASP的激活在体内诱导丝状伪足的形成。相比之下，普遍表达的WAVE2形式在Rac下游被激活，导致片状伪足的形成。在这种情况下，IRSp53通过形成三元Rac-IRSp53-WAVE2复合物将信号从Rac传递给WAVE2。因此，在Cdc42下游或由WISH独立激活的N-WASP诱导丝状伪足的形成，而通过Rac下游的IRSp53激活的WAVE2诱导片状伪足的形成。
