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

Han Seok Ko, Yunjong Lee, Joo Ho Shin, Senthilkumar S. Karuppagounder, Bharathi Shrikanth Gadad, Anthony J. Koleske, Olga Pletnikova, Juan C. Troncoso, Valina L. Dawson, Ted M. Dawson

Research output: Contribution to journalArticle

156 Scopus citations

Abstract

Mutations in PARK2/Parkin, which encodes a ubiquitin E3 ligase, cause autosomal recessive Parkinsondisease (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 post-translational 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.

Original languageEnglish (US)
Pages (from-to)16691-16696
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number38
DOIs
StatePublished - Sep 21 2010

Keywords

  • AIMP2
  • Parkinson disease
  • STI-571
  • Ubiquitin

ASJC Scopus subject areas

  • General

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    Ko, H. S., Lee, Y., Shin, J. H., Karuppagounder, S. S., Gadad, B. S., Koleske, A. J., Pletnikova, O., Troncoso, J. C., Dawson, V. L., & Dawson, T. M. (2010). Phosphorylation by the c-Abl protein tyrosine kinase inhibits parkin's ubiquitination and protective function. Proceedings of the National Academy of Sciences of the United States of America, 107(38), 16691-16696. https://doi.org/10.1073/pnas.1006083107