Weed S A, Du Y, Parsons J T
Department of Microbiology, Health Sciences Center, University of Virginia, Charlottesville, Virginia 22908, USA.
J Cell Sci. 1998 Aug;111 ( Pt 16):2433-43. doi: 10.1242/jcs.111.16.2433.
Small GTPases of the Rho family regulate signaling pathways that control actin cytoskeletal structures. In Swiss 3T3 cells, RhoA activation leads to stress fiber and focal adhesion formation, Rac1 to lamellipoda and membrane ruffles, and Cdc42 to microspikes and filopodia. Several downstream molecules mediating these effects have been recently identified. In this report we provide evidence that the intracellular localization of the actin binding protein cortactin, a Src kinase substrate, is regulated by the activation of Rac1. Cortactin redistributes from the cytoplasm into membrane ruffles as a result of growth factor-induced Rac1 activation, and this translocation is blocked by expression of dominant negative Rac1N17. Expression of constitutively active Rac1L61 evoked the translocation of cortactin from cytoplasmic pools into peripheral membrane ruffles. Expression of mutant forms of the serine/threonine kinase PAK1, a downstream effector of Rac1 and Cdc42 recently demonstrated to trigger cortical actin polymerization and membrane ruffling, also led to the translocation of cortactin to the cell cortex, although this was effectively blocked by coexpression of Rac1N17. Collectively these data provide evidence for cortactin as a putative target of Rac1-induced signal transduction events involved in membrane ruffling and lamellipodia formation.
Rho家族的小GTP酶调节控制肌动蛋白细胞骨架结构的信号通路。在瑞士3T3细胞中，RhoA激活导致应力纤维和粘着斑形成，Rac1激活导致片状伪足和膜皱褶形成，Cdc42激活导致微刺和丝状伪足形成。最近已经鉴定出几种介导这些效应的下游分子。在本报告中，我们提供证据表明，肌动蛋白结合蛋白cortactin（一种Src激酶底物）的细胞内定位受Rac1激活的调节。由于生长因子诱导的Rac1激活，cortactin从细胞质重新分布到膜皱褶中，并且这种易位被显性负性Rac1N17的表达所阻断。组成型活性Rac1L61的表达引起cortactin从细胞质池转运到外周膜皱褶中。丝氨酸/苏氨酸激酶PAK1（Rac1和Cdc42的下游效应物，最近证明可触发皮质肌动蛋白聚合和膜皱褶）的突变形式的表达也导致cortactin转运到细胞皮质，尽管这被Rac1N17的共表达有效阻断。这些数据共同为cortactin作为参与膜皱褶和片状伪足形成的Rac1诱导信号转导事件的假定靶点提供了证据。
