RGD Reference Report - Phosphorylation by the c-Abl protein tyrosine kinase inhibits parkin's ubiquitination and protective function. - Rat Genome Database

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

Authors: Ko, HS  Lee, Y  Shin, JH  Karuppagounder, SS  Gadad, BS  Koleske, AJ  Pletnikova, O  Troncoso, JC  Dawson, VL  Dawson, TM 
Citation: Ko HS, etal., Proc Natl Acad Sci U S A. 2010 Sep 21;107(38):16691-6. doi: 10.1073/pnas.1006083107. Epub 2010 Sep 7.
RGD ID: 8693409
Pubmed: PMID:20823226   (View Abstract at PubMed)
PMCID: PMC2944759   (View Article at PubMed Central)
DOI: DOI:10.1073/pnas.1006083107   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Parkinson's disease  IEP 8693409protein:increased phosphorylation:striatum:RGD 
Parkinson's disease  ISOABL1 (Homo sapiens)8693409; 8693409protein:increased phosphorylation:striatum:RGD 
Parkinson's disease  IEP 8693409protein:increased tyrosine-phosphorylation:substantia nigra more ...RGD 
Parkinson's disease  ISOPRKN (Homo sapiens)8693409; 8693409protein:increased tyrosine-phosphorylation:substantia nigra more ...RGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
negative regulation of neuron apoptotic process acts_upstream_of_or_withinIGIUniProtKB:Q32PX28693409PMID:20823226MGI 
positive regulation of neuron apoptotic process acts_upstream_of_or_withinIDA 8693409PMID:20823226MGI 

Objects Annotated

Genes (Rattus norvegicus)
Abl1  (ABL proto-oncogene 1, non-receptor tyrosine kinase)
Aimp2  (aminoacyl tRNA synthetase complex-interacting multifunctional protein 2)
Prkn  (parkin RBR E3 ubiquitin protein ligase)

Genes (Mus musculus)
Abl1  (c-abl oncogene 1, non-receptor tyrosine kinase)
Prkn  (parkin RBR E3 ubiquitin protein ligase)

Genes (Homo sapiens)
ABL1  (ABL proto-oncogene 1, non-receptor tyrosine kinase)
PRKN  (parkin RBR E3 ubiquitin protein ligase)


Additional Information