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PMID: 19880420 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Phosphorylation of parkin by Parkinson disease-linked kinase PINK1 activates parkin E3 ligase function and NF-kappaB signaling.

Human molecular genetics ·Vol. 19 ·No. 2 ·2010-01-15 ·Pages 352-63

Sha D, Chin LS, Li L

Abstract

Mutations in PTEN-induced putative kinase 1 (PINK1) or parkin cause autosomal recessive forms of Parkinson disease (PD), but how these mutations trigger neurodegeneration is poorly understood and the exact functional relationship between PINK1 and parkin remains unclear. Here, we report that PINK1 regulates the E3 ubiquitin-protein ligase function of parkin through direct phosphorylation. We find that phosphorylation of parkin by PINK1 activates parkin E3 ligase function for catalyzing K63-linked polyubiquitination and enhances parkin-mediated ubiquitin signaling through the IkappaB kinase/nuclear factor kappaB (NF-kappaB) pathway. Furthermore, the ability of PINK1 to promote parkin phosphorylation and activate parkin-mediated ubiquitin signaling is impaired by PD-linked pathogenic PINK1 mutations. Our findings support a direct link between PINK1-mediated phosphorylation and parkin-mediated ubiquitin signaling and implicate the deregulation of the PINK1/parkin/NF-kappaB neuroprotective signaling pathway in the pathogenesis of PD.

MeSH Terms
Cell Line Enzyme Activation Humans Mutation NF-kappa B/genetics,metabolism Parkinson Disease/enzymology,genetics,metabolism Phosphorylation Protein Binding Protein Kinases/chemistry,genetics,metabolism Protein Structure, Tertiary Signal Transduction Ubiquitin/metabolism Ubiquitin-Protein Ligases/chemistry,genetics,metabolism
Chemicals
NF-kappa B Ubiquitin Ubiquitin-Protein Ligases parkin protein Protein Kinases PTEN-induced putative kinase
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Sha Di
Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Chin Lih-Shen
Li Lian
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Article Info
Journal
Human molecular genetics
Abbr.
Hum Mol Genet
ISSN
1460-2083
DOI
10.1093/hmg/ddp501
Published
2010-01-15
Epub
2009-00-30
Pages
352-63
Language
English
Region
England
NLM ID
9208958
PMCID
PMC2796895
Subset
IM
Grants
NIEHS NIH HHS · ES015813 · United States
NIA NIH HHS · R01 AG034126 · United States
NIA NIH HHS · AG021489 · United States
NINDS NIH HHS · NS050650 · United States
NIA NIH HHS · AG034126 · United States
NIGMS NIH HHS · GM082828-02S1 · United States
NIGMS NIH HHS · GM082828 · United States
External Links
PubMed source DOI: 10.1093/hmg/ddp501 PMC Full Text View journal details
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