Laboratory of Neuronal Cell Morphogenesis, Graduate School of Biological Sciences, Nara Institute of Science and Technology, Ikoma, Nara 630-0192, Japan.
Curr Biol. 2013 Mar 18;23(6):529-34. doi: 10.1016/j.cub.2013.02.017. Epub 2013 Feb 28.
Soluble guidance cues can direct cellular protrusion and migration by modulating adhesion and cytoskeletal dynamics. Actin filaments (F-actins) polymerize at the leading edge of motile cells and depolymerize proximally [1, 2]; this, together with myosin II activity, induces retrograde flow of F-actins [3-5]. It has been proposed that the traction forces underlying cellular motility may be regulated by the modulation of coupling efficiency between F-actin flow and the extracellular substrate via "clutch" molecules [6-10]. However, how cell signaling controls the coupling efficiency remains unknown. Shootin1 functions as a linker molecule that couples F-actin retrograde flow and the substrate at neuronal growth cones to promote axon outgrowth [11]. Here we show that shootin1 is located at a critical interface, transducing a chemical signal into traction forces for axon outgrowth. We found that a chemoattractant, netrin-1, positively regulates traction forces at axonal growth cones via Pak1-mediated shootin1 phosphorylation. This phosphorylation enhanced the interaction between shootin1 and F-actin retrograde flow, thereby promoting F-actin-substrate coupling, force generation, and concomitant filopodium extension and axon outgrowth. These results suggest that dynamic actin-substrate coupling can transduce chemical signals into mechanical forces to control cellular motility and provide a molecular-level description of how this transduction may occur.
可溶性导向分子可以通过调节黏附和细胞骨架动力学来指导细胞突起和迁移。肌动蛋白丝（F-肌动蛋白）在运动细胞的前缘聚合，并在近端解聚[1,2]；这与肌球蛋白 II 的活性一起，诱导 F-肌动蛋白的逆行流动[3-5]。有人提出，细胞运动的基础牵引力可能通过“离合器”分子调节 F-肌动蛋白流动和细胞外基质之间的偶联效率来调节[6-10]。然而，细胞信号如何控制偶联效率尚不清楚。Shootin1 作为一种连接分子，将 F-肌动蛋白的逆行流动和神经元生长锥中的基质连接起来，促进轴突的生长[11]。在这里，我们表明 shootin1 位于一个关键界面，将化学信号转导为用于轴突生长的牵引力。我们发现，趋化因子 netrin-1 通过 Pak1 介导的 shootin1 磷酸化正向调节轴突生长锥的牵引力。这种磷酸化增强了 shootin1 与 F-肌动蛋白逆行流动之间的相互作用，从而促进 F-肌动蛋白-基质偶联、力的产生以及随之而来的丝状伪足延伸和轴突生长。这些结果表明，动态肌动蛋白-基质偶联可以将化学信号转导为机械力，以控制细胞运动，并提供这种转导如何发生的分子水平描述。
