PDZ-RhoGEF ubiquitination by Cullin3-KLHL20 controls neurotrophin-induced neurite outgrowth
Resource
JOURNAL OF CELL BIOLOGY, 193(6), 985-994
Journal
JOURNAL OF CELL BIOLOGY
Journal Volume
193
Journal Issue
6
Pages
985-994
Date Issued
2011
Date
2011
Author(s)
Lin, Mei-Yao
Lin, Yu-Min
Kao, Te-chan
Chuang, Hsiang-Hao
Chen, Ruey-Hwa
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.
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journal article
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