分子醫學研究所LIN, YU-MINYU-MINLINKAO, TE-CHANTE-CHANKAOCHEN, RUEY-HWARUEY-HWACHEN2012-07-052018-07-092012-07-052018-07-092011http://ntur.lib.ntu.edu.tw//handle/246246/240679The induction of neurite outgrowth and arborization is critical for developmental and regenerative processes. In this paper, we report that the BTB-kelch protein KLHL20 promoted neurite outgrowth and arborization in hippocampal and cortical neurons through its interaction with Cullin3 to form a ubiquitin ligase complex. This complex targeted PDZ- Rho guanine nucleotide exchange factor RhoGEF, a protein abundantly expressed in the brain, for ubiquitin-dependent proteolysis, thereby restricting RhoA activity and facilitating growth cone spreading and neurite outgrowth. Importantly, targeting PDZ-RhoGEF to KLHL20 required PDZ- RhoGEF phosphorylation by p38 mitogen-activated protein kinase. In response to p 38-activating neurotrophins, such as brain-derived neurotrophic factor and neurotrophin-3, KLHL 20-mediated PDZ-RhoGEF destruction was potentiated, leading to neurotrophin-induced neurite outgrowth. Our study identified a ubiquitin-dependent pathway that targets PDZ- RhoGEF destruction to facilitate neurite outgrowth and indicates a key role of this pathway in neurotrophin-induced neuronal morphogenesis.en-US