Phosphorylation by the c-Abl protein tyrosine kinase inhibits parkin's ubiquitination and protective function

• DOI: 10.1073/pnas.1006083107
• Publication Date: 2010-09-08T02:21:32Z
• Authors: Han Seok Ko; Yunjong Lee; Joo-Ho Shin; Senthilkumar S. K...; Bharathi Shrikant...; Anthony J. Koleske; Olga Pletnikova; Juan C. Troncoso; Valina L. Dawson; Ted M. Dawson
• Keywords: Mice, Knockout; Neurons; 0301 basic medicine; Cell Death; Dopamine; Recombinant Fusion Proteins; Molecular Sequence Data; Brain; Parkinson Disease; In Vitro Techniques; PC12 Cells; Cell Line; Rats; 3. Good health; Gene Knockout Techniques; Mice; 03 medical and health sciences; Mutation; Animals; Humans; Amino Acid Sequence; Phosphorylation; Proto-Oncogene Proteins c-abl

Mutations in PARK2/Parkin , which encodes a ubiquitin E3 ligase, cause autosomal recessive Parkinson disease (PD). Here we show that the nonreceptor tyrosine kinase c-Abl phosphorylates 143 of parkin, inhibiting parkin's ligase activity and protective function. is activated by dopaminergic stress neurotoxins, 1-methyl-4-phenylpyridinium (MPP + ) vitro vivo 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), leading to parkin inactivation, accumulation substrates aminoacyl-tRNA synthetase-interacting multifunctional protein type 2 (AIMP2) (p38/JTV-1) fuse-binding 1 (FBP1), cell death. STI-571, c-Abl-family inhibitor, prevents phosphorylation maintaining catalytically active state. STI-571’s effects require as shRNA knockdown STI-571 protection. Conditional knockout nervous system also its substrates, subsequent neurotoxicity response MPTP intoxication. In human postmortem PD brain, active, tyrosine-phosphorylated, AIMP2 FBP1 accumulate substantia nigra striatum. Thus, major posttranslational modification inhibits function, possibly contributing pathogenesis sporadic PD. Moreover, inhibition may be neuroprotective approach treatment