Article

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: 9.81). 09/2010; 107(38):16691-6. DOI: 10.1073/pnas.1006083107
Source: PubMed

ABSTRACT 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, Aug 13, 2015
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    • "The pharmacological inhibition of c-Abl is also emerging as an attractive therapeutic strategy, as it was found to be neuroprotective in animal models of PD (Ko et al., 2010; Imam et al., 2011, 2013; Hebron et al., 2013a; Mahul-Mellier et al., 2014), by promoting aSyn degradation (Hebron et al., 2013a,b; Mahul- Mellier et al., 2014). Interestingly, c-Abl inhibition also targets hyperphosphorylated tau for degradation (Hebron et al., 2013a) and inhibits β-amyloid production in rat neuronal primary cultures and in guinea pig brains (Netzer et al., 2003). "
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    Frontiers in Molecular Neuroscience 05/2014; 7. DOI:10.3389/fnmol.2014.00042 · 4.08 Impact Factor
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    • "In this study, we provide a novel finding that in MPTP mice, striatal motor behaviors were normalized by systemic administration of nilotinib, a drug that is now clinically used to treat chronic myeloid leukemia (Weisberg et al., 2006; Blay and von Mehren, 2011). Together with the reported experimental findings that nilotinib (Hebron et al., 2013) and other c-Abl inhibitors (Ko et al., 2010; Imam et al., 2011, 2013) also play a protective role against the neurodegeneration of dopamine-producing cells in the substantia nigra of mice, our results suggest that nilotinib may serve as an alternative agent for attenuating motor symptoms and disease progression of PD. "
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    • "Abl activation inhibits the E3 ubiquitin ligase activity of parkin, and Abl inhibition induces parkin protective function in Parkinson's disease (PD) models (Imam et al, 2011). Parkin is inactivated in the nigrostriatum of post‐mortem sporadic PD patients (Ko et al, 2010; Lonskaya et al, 2012a), and decreased parkin solubility is associated with defects in autophagic clearance of b‐ amyloid and p‐Tau in post‐mortem Alzheimer's disease (AD) brains (Lonskaya et al, 2012c). Parkin mediates autophagic degradation of defective mitochondria (mitophagy) (Geisler et al, 2010; Narendra et al, 2008; Park et al, 2009; Vives‐Bauza et al, 2010), and clears autophagic vacuoles (AVs) in AD and PD models (Khandelwal et al, 2011; Lonskaya et al, 2012a; Lonskaya et al, 2012c), while parkin deletion exacerbates amyloid pathology in AD models (Perucho et al, 2010; Rodriguez‐Navarro et al, 2008). "
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