title: PDZ-RhoGEF ubiquitination by Cullin3-KLHL20 controls neurotrophin-induced neurite outgrowth.
abstract: 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.
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei 10617, Taiwan.
authors.forename: Mei-Yao
authors.initials: MY
authors.lastname: Lin
authors.forename: Yu-Min
authors.initials: YM
authors.lastname: Lin
authors.forename: Te-chan
authors.initials: TC
authors.lastname: Kao
authors.forename: Hsiang-Hao
authors.initials: HH
authors.lastname: Chuang
authors.forename: Ruey-Hwa
authors.initials: RH
authors.lastname: Chen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D009414:Nerve Growth Factors / Q000378:metabolism*; D016501:Neurites / Q000502:physiology* / Q000648:ultrastructure; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D054731:PDZ Domains; D051381:Rats; D064067:Rho Guanine Nucleotide Exchange Factors; D020798:Two-Hybrid System Techniques; D054875:Ubiquitination; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C561111:Cul3 protein, rat; D044842:Cullin Proteins; D020662:Guanine Nucleotide Exchange Factors; C550011:KLHL20 protein, human; D009414:Nerve Growth Factors; D064067:Rho Guanine Nucleotide Exchange Factors; D048051:p38 Mitogen-Activated Protein Kinases; D020742:rhoA GTP-Binding Protein