Yamauchi Junji, Miyamoto Yuki, Sanbe Atsushi, Tanoue Akito
Department of Pharmacology, National Research Institute for Child Health and Development, 2-10-1 Oukura, Setagaya, Tokyo 157-8535, Japan.
Exp Cell Res. 2006 Sep 10;312(15):2954-61. doi: 10.1016/j.yexcr.2006.05.016. Epub 2006 Jun 7.
Neurons extend neurites from the cell body before formation of the polarized processes of an axon and dendrites. Neurite outgrowth involves remodeling of the cytoskeletal components, which are initially regulated by small GTPases of the Rho family. Here we show that c-Jun N-terminal kinase (JNK), which is controlled by Rho GTPases Rac1 and Cdc42, is activated following neurite extension in mouse N1E-115 neuroblastoma cells as a model. The extension is inhibited by JNK inhibitors (SP600125 and the small JNK-binding peptide) and Clostridium difficile Toxin B, the inhibitor for Rho GTPases. Additionally, paxillin, the multifunctional focal adhesion protein, is phosphorylated at Ser 178 by upregulation of the Rac1/Cdc42/JNK cascade. Conversely, transfection of the paxillin construct harboring the Ser 178-to-Ala mutation into cells inhibits neurite extension. Taken together, these results suggest the novel role of the Rac1/Cdc42/JNK signaling cascade in neurite extension and indicate that the downstream target paxillin may be one of the convergent points of various signaling pathways underlying neurite extension.
在轴突和树突的极化过程形成之前，神经元从细胞体延伸出神经突。神经突生长涉及细胞骨架成分的重塑，其最初由Rho家族的小GTP酶调节。在这里，我们以小鼠N1E-115神经母细胞瘤细胞为模型表明，由Rho GTP酶Rac1和Cdc42控制的c-Jun氨基末端激酶（JNK）在神经突延伸后被激活。这种延伸受到JNK抑制剂（SP600125和小的JNK结合肽）以及Rho GTP酶抑制剂艰难梭菌毒素B的抑制。此外，多功能粘着斑蛋白桩蛋白在Ser 178位点被Rac1/Cdc42/JNK级联的上调磷酸化。相反，将携带Ser 178突变为Ala突变的桩蛋白构建体转染到细胞中会抑制神经突延伸。综上所述，这些结果表明Rac1/Cdc42/JNK信号级联在神经突延伸中具有新作用，并表明下游靶点桩蛋白可能是神经突延伸潜在的各种信号通路的汇聚点之一。
