title: Conversion of a signal into forces for axon outgrowth through Pak1-mediated shootin1 phosphorylation.
abstract: 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.
authors: Laboratory of Neuronal Cell Morphogenesis, Graduate School of Biological Sciences, Nara Institute of Science and Technology, Ikoma, Nara 630-0192, Japan.
authors: Michinori
authors: M
authors: Toriyama
authors: Satoshi
authors: S
authors: Kozawa
authors: Yuichi
authors: Y
authors: Sakumura
authors: Naoyuki
authors: N
authors: Inagaki
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D020439:Growth Cones / Q000502:physiology*; D006624:Hippocampus / Q000254:growth & development / Q000502:physiology; D013058:Mass Spectrometry; D009414:Nerve Growth Factors / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D000075388:Netrin-1; D010766:Phosphorylation; D051381:Rats; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D054462:p21-Activated Kinases / Q000378:metabolism*
chemical_list: D000199:Actins; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; C000617354:Ntn1 protein, rat; C514975:Shtn1 protein, rat; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1; C515906:Pak1 protein, rat; D054462:p21-Activated Kinases