Phosphorylation by the c-Abl protein tyrosine kinase inhibits Parkin’s ubiquitination and protective function

Neuroregeneration Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 09/2010; 107(38):16691-6. DOI: 10.1073/pnas.1006083107
Source: PubMed


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.

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Available from: Bharathi Shrikanth Gadad
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    • "Interestingly, treatment with the c- Abl inhibitor Imatinib decreases apoptosis of Purkinje cerebellar neurons, improving locomotor abilities and increasing the survival rates of Npc1 −/− mice [35]. In addition, c-Abl activity has been implicated in several neurodegenerative disorders such as AD [36] [37], Parkinson's disease [38] and amyotrophic lateral sclerosis [39]. Finally, c-Abl-overexpressing mice show severe neurodegeneration [40]. "
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    • "Parkin ubiquitination ligase activity is intrinsically repressed due to structural features of the protein that occlude the E2 and catalytic sites [34]. Enzyme activity is regulated by mitochondrial relocalization, post-translational modifications and ligand binding to the ubiquitin-like (Ubl) domain [31]–[33], [35]–[38]. In addition, the enzyme can be constitutively activated either by deletion of amino-terminal sequences containing the Ubl and zinc-finger RING0 domains or by various missense mutations responsible for juvenile autosomal recessive PD [34]. "
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    ABSTRACT: Parkinson's disease (PD) is a neurodegenerative disorder of complex etiology characterized by the selective loss of dopaminergic neurons, particularly in the substantia nigra. Parkin, a tightly regulated E3 ubiquitin ligase, promotes the survival of dopaminergic neurons in both PD and Parkinsonian syndromes induced by acute exposures to neurotoxic agents. The present study assessed the potential of cell-permeable parkin (CP-Parkin) as a neuroprotective agent. Cellular uptake and tissue penetration of recombinant, enzymatically active parkin was markedly enhanced by the addition of a hydrophobic macromolecule transduction domain (MTD). The resulting CP-Parkin proteins (HPM13 and PM10) suppressed dopaminergic neuronal toxicity in cells and mice exposed to 6-hydroxydopamine (6-OHDH) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). These included enhanced survival and dopamine expression in cultured CATH.a and SH-SY5Y neuronal cells; and protection against MPTP-induced damage in mice, notably preservation of tyrosine hydroxylase-positive cells with enhanced dopamine expression in the striatum and midbrain, and preservation of gross motor function. These results demonstrate that CP-Parkin proteins can compensate for intrinsic limitations in the parkin response and provide a therapeutic strategy to augment parkin activity in vivo.
    Full-text · Article · Jul 2014 · PLoS ONE
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    • "Thus, the non-tyrosine receptor kinase c-Abl mediates dopaminergic stress or dopaminergic neurotoxin-induced tyrosine 143 phosphorylation of parkin. This modification leads to the inactivation of parkin, the subsequent accumulation of pathogenic parkin substrates, and to the eventual death of dopaminergic cells [59,60]. Interaction of parkin with 14-3-3eta was shown to negatively regulate its activity. "
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