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

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

Pubmed ID: 20823226


  • Ko HS
  • Lee Y
  • Shin JH
  • Karuppagounder SS
  • Gadad BS
  • Koleske AJ
  • Pletnikova O
  • Troncoso JC
  • Dawson VL
  • Dawson TM


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

September 21, 2010

Associated Grants

  • Agency: NINDS NIH HHS, Id: NS048206
  • Agency: NINDS NIH HHS, Id: NS051764
  • Agency: NINDS NIH HHS, Id: NS38377
  • Agency: NINDS NIH HHS, Id: NS39475
  • Agency: NINDS NIH HHS, Id: P50 NS038377
  • Agency: NINDS NIH HHS, Id: R01 NS039475

Mesh Terms

  • Amino Acid Sequence
  • Animals
  • Brain
  • Cell Death
  • Cell Line
  • Dopamine
  • Gene Knockout Techniques
  • Humans
  • In Vitro Techniques
  • Mice
  • Mice, Knockout
  • Molecular Sequence Data
  • Mutation
  • Neurons
  • PC12 Cells
  • Parkinson Disease
  • Phosphorylation
  • Proto-Oncogene Proteins c-abl
  • Rats
  • Recombinant Fusion Proteins
  • Stress, Physiological
  • Ubiquitin-Protein Ligases
  • Ubiquitination