Combined kinase inhibition modulates parkin inactivation

Torre, Elena Rubio de la; Luzón-Toro, Berta; Forte-Lago, Irene; Minguez-Castellanos, Adolfo; Ferrer, Isidró; Hilfiker, Sabine

doi:10.1093/hmg/ddn407

Cited by 32 publications

(45 citation statements)

References 52 publications

(62 reference statements)

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“…Parkin's E3 ligase activity and protective function are regulated by posttranslational modifications including S-nitrosylation (15), phosphorylation (16,17), and dopamine conjugation (18). Here we report functional regulation of parkin activity by phosphorylation of tyrosine 143 by c-Abl.…”

mentioning

confidence: 82%

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

Ko¹,

Lee²,

Shin³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

237

279

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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.is a common neurodegenerative disorder characterized by the loss of dopamine (DA) neurons and protein accumulation in intracellular inclusions designated as Lewy bodies and Lewy neurites (1). Although the majority of PD is sporadic in nature, rare familial mutations are providing insight into this chronic, progressive neurodegenerative disease. Mutations in α-synuclein and LRRK2 cause autosomal-dominant PD, whereas mutations in DJ-1, PINK1, and parkin result in autosomal-recessive PD (2). Parkin mutations are the most common cause of autosomal-recessive PD and, for the most part, PD due to parkin mutations is indistinguishable from sporadic PD (3). Parkin is a ubiquitin E3 ligase, and familial mutations are thought to impair the E3 ligase activity of parkin (4, 5).Parkin ubiquitinates proteins via monoubiquitination or polyubiquitination using either lysine 48 (K48) or lysine 63 (K63). Monoubiquitination by parkin is thought to regulate receptor trafficking (6). Polyubiquitination by parkin via K48 is thought to mediate proteasomal degradation (7,8), whereas polyubiquitination by K63 may be involved in inclusion formation (9). Parkin's differential ubiquitination properties are likely to be regulated by different ubiquitin-conjugating E2s and other associated proteins or regulatory processes (3). A number of putative parkin substrates have been identified (for a review, see ref.3). Aminoacyl-tRNA synthetaseinteracting multifunctional protein type 2 (AIMP2) (p38/JTV-1) and fuse-binding protein 1 (FB...

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mentioning

confidence: 82%

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

Ko¹,

Lee²,

Shin³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

237

279

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“…Although numerous papers have reported Parkin phosphorylation, the phosphorylation site(s) remains debatable. To date, Ser-65 (56, 61), Ser-101 (62, 63), Ser-108 (64), Ser-127 (63), Ser-131 (56,62,63,65), Ser-136 (62, 65), Thr-175 (66), Thr-217 (66), Ser-296 (62), and Ser-378 (62, 63) have been reported as phosphorylation sites. We consequently serially substituted these Ser/Thr residues with Asp.…”

Section: Pink1 Is Essential For Formation Of the Ester-linked Parkinumentioning

confidence: 99%

Parkin-catalyzed Ubiquitin-Ester Transfer Is Triggered by PINK1-dependent Phosphorylation

Iguchi

Kujuro

Okatsu

et al. 2013

Journal of Biological Chemistry

176

150

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Background: Parkin is a ubiquitin ligase activated by a decrease in the mitochondrial membrane potential (⌬⌿m). However, details regarding its mechanism remain limited. Results: PINK1-dependent phosphorylation of Parkin at Ser-65 following dissipation of ⌬⌿m triggers ubiquitin-ester transfer by the RING2 domain of Parkin to Cys-431. Conclusion: Parkin catalyzes trans-(ubiquitin-thioester)ification upon PINK1-dependent phosphorylation. Significance: The molecular process of Parkin-catalyzed ubiquitylation has been determined.

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“…Parkin is phosphorylated by the mitochondrial kinase PINK1 at Ser65 (Kondapalli, Kazlauskaite et al 2012) (Shiba-Fukushima, Imai et al 2012, Iguchi, Kujuro et al 2013), however, other serines have also been identified as phosphorylation sites in parkin (Yamamoto, Friedlein et al 2005, Rubio de la Torre, Luzon-Toro et al 2009). Phosphorylation of parkin by other kinases at other sites may also be part of a greater network of proteins regulation of its ligase activity (Yamamoto, Friedlein et al 2005, Rubio de la Torre, Luzon-Toro et al 2009). Given that cytosolic parkin has been implicated in virtually all non-mitophagic functions and substrates of parkin, there are likely other kinases that play a role in parkin activation.…”

Section: Parkin Targeted Therapy For Pd and Other Neurodegenerative Dmentioning

confidence: 99%

Pathologic and therapeutic implications for the cell biology of parkin

Charan

LaVoie

2015

Molecular and Cellular Neuroscience

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Mutations in the E3 ligase parkin are the most common cause of autosomal recessive Parkinson's disease (PD), but it is believed that parkin dysfunction may also contribute to idiopathic PD. Since its discovery, parkin has been implicated in supporting multiple neuroprotective pathways, many revolving around the maintenance of mitochondrial health quality control and governance of cell survival. Recent advances across the structure, biochemistry, and cell biology of parkin have provided great insights into the etiology of parkin-linked and idiopathic PD and may ultimately generate novel therapeutic strategies to slow or halt disease progression. This review describes the various pathways in which parkin acts and the mechanisms by which parkin may be targeted for therapeutic intervention.

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Combined kinase inhibition modulates parkin inactivation

Cited by 32 publications

References 52 publications

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

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

Parkin-catalyzed Ubiquitin-Ester Transfer Is Triggered by PINK1-dependent Phosphorylation

Pathologic and therapeutic implications for the cell biology of parkin

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