Pdz-Rhogef Ubiquitination by Cullin3-Klhl20 Controls Neurotrophin-Induced Neurite Outgrowth
Resource
JOURNAL OF CELL BIOLOGY v.193 n.6 pp.985-994
Journal
JOURNAL OF CELL BIOLOGY
Journal Volume
v.193
Journal Issue
n.6
Pages
985-994
Date Issued
2011
Date
2011
Author(s)
LIN, YU-MIN
KAO, TE-CHAN
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 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.