PDZ-RhoGEF ubiquitination by Cullin3–KLHL20 controls neurotrophin-induced neurite outgrowth

• Published in: The Journal of cell biology Vol. 193; no. 6; pp. 985 - 994
• Main Authors: Lin, Mei-Yao, Lin, Yu-Min, Kao, Te-chan, Chuang, Hsiang-Hao, Chen, Ruey-Hwa
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 13.06.2011; The Rockefeller University Press
• Subjects: Animals; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell growth; Cells, Cultured; Cullin Proteins - genetics; Cullin Proteins - metabolism; Guanine Nucleotide Exchange Factors - genetics; Guanine Nucleotide Exchange Factors - metabolism; HEK293 Cells; HeLa Cells; Humans; Morphology; Nerve Growth Factors - metabolism; Neurites - physiology; Neurites - ultrastructure; Neurons; Neurons - cytology; Neurons - metabolism; p38 Mitogen-Activated Protein Kinases - metabolism; PDZ Domains; Proteins; Rats; Rho Guanine Nucleotide Exchange Factors; rhoA GTP-Binding Protein - genetics; rhoA GTP-Binding Protein - metabolism; Studies; Two-Hybrid System Techniques; Ubiquitination
• ISSN: 0021-9525; 1540-8140; 1540-8140
• DOI: 10.1083/jcb.201103015

The 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 p38-activating neurotrophins, such as brain-derived neurotrophic factor and neurotrophin-3, KLHL20-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.