Jin Eun-Ju, Ko Hyo Rim, Hwang Inwoo, Kim Byeong-Seong, Choi Jeong-Yun, Park Kye Won, Cho Sung-Woo, Ahn Jee-Yin
Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, 16419, Korea.
Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwon, 16419, Korea.
Sci Rep. 2018 Feb 7;8(1):2557. doi: 10.1038/s41598-018-20755-w.
Neurite growth is controlled by a complex molecular signaling network that regulates filamentous actin (F-actin) dynamics at the growth cone. The evolutionarily conserved ezrin, radixin, and moesin family of proteins tether F-actin to the cell membrane when phosphorylated at a conserved threonine residue and modulate neurite outgrowth. Here we show that Akt binds to and phosphorylates a threonine 573 residue on radixin. Akt-mediated phosphorylation protects radixin from ubiquitin-dependent proteasomal degradation, thereby enhancing radixin protein stability, which permits proper neurite outgrowth and growth cone formation. Conversely, the inhibition of Akt kinase or disruption of Akt-dependent phosphorylation reduces the binding affinity of radixin to F-actin as well as lowers radixin protein levels, resulting in decreased neurite outgrowth and growth cone formation. Our findings suggest that Akt signaling regulates neurite outgrowth by stabilizing radixin interactions with F-actin, thus facilitating local F-actin dynamics.
神经突生长由一个复杂的分子信号网络控制，该网络调节生长锥处的丝状肌动蛋白（F-肌动蛋白）动力学。进化上保守的埃兹蛋白、根蛋白和膜突蛋白家族的蛋白质在保守的苏氨酸残基磷酸化时，将F-肌动蛋白拴系到细胞膜上，并调节神经突的生长。在这里，我们表明Akt与根蛋白上的苏氨酸573残基结合并使其磷酸化。Akt介导的磷酸化保护根蛋白免受泛素依赖性蛋白酶体降解，从而增强根蛋白的稳定性，这允许适当的神经突生长和生长锥形成。相反，抑制Akt激酶或破坏Akt依赖性磷酸化会降低根蛋白与F-肌动蛋白的结合亲和力，并降低根蛋白水平，导致神经突生长和生长锥形成减少。我们的研究结果表明，Akt信号通过稳定根蛋白与F-肌动蛋白的相互作用来调节神经突生长，从而促进局部F-肌动蛋白动力学。
