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.
Ko
Han Seok
HS
Neuroregeneration Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Lee
Yunjong
Y
Shin
Joo-Ho
JH
Karuppagounder
Senthilkumar S
SS
Gadad
Bharathi Shrikanth
BS
Koleske
Anthony J
AJ
Pletnikova
Olga
O
Troncoso
Juan C
JC
Dawson
Valina L
VL
Dawson
Ted M
TM
D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000378:metabolism; D016923:Cell Death; D002460:Cell Line; D004298:Dopamine / Q000378:metabolism; D055786:Gene Knockout Techniques; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009154:Mutation; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D016716:PC12 Cells; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism*; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013312:Stress, Physiological; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
D011993:Recombinant Fusion Proteins; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D016315:Proto-Oncogene Proteins c-abl; D004298:Dopamine
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