Oxidative stress‐induced phosphorylation, degradation and aggregation of α‐synuclein are linked to upregulated CK2 and cathepsin D

Takahashi, Makio; Ko, Li Wen; Kulathingal, Jayanarayan; Jiang, Peizhou; Sevlever, Daniel; Yen, Shu Hui

doi:10.1111/j.1460-9568.2007.05736.x

Cited by 110 publications

(107 citation statements)

References 37 publications

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“…However, it remains unclear, how, when and where the CK2 kinase activity is regulated in cells (Miyata, 2009). Changes in CK2 activity induced by various stimuli are correlated with its protein levels (Takahashi et al, 2007). CK2 is normally expressed at a higher level than the catalytic subunits ( and Ј) of CK2, allowing some CK2 to be incorporated into tetramers and stabilized, whereas the excess CK2 is rapidly degraded with a half-life of less than 1 hour (Luscher and Litchfield, 1994).…”

Section: Ck2 Is a Regulator Of Hdac6 Catalytic Activity And A Bridge mentioning

confidence: 99%

Protein kinase CK2 regulates the formation and clearance of aggresomes in response to stress

Watabe

Nakaki

2011

Journal of Cell Science

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SummaryMisfolded protein aggregates elicit a stress response, and their clearance is crucial for cell survival. These aggregates are transported by cytoplasmic deacetylase HDAC6 and dynein motors to the aggresome via the microtubule network, and are removed by autophagic degradation. HDAC6 activity is necessary for both the transport and clearance of protein aggregates. However, the cellular factors that regulate HDAC6 activity remain unknown. Here we show that protein kinase CK2 is a crucial modulator of HDAC6 activity because CK2 directly phosphorylates HDAC6 and increases cytoplasmic deacetylase activity. Indeed, cells that expressed HDAC6 mutated at Ser458, a CK2-mediated phosphorylation site, failed to both form and clear aggresomes, and increased cytotoxicity. Interestingly, Ser458 is conserved only in higher primates, such as human and chimpanzee, but not in the rhesus macaque. These findings identify CK2 as a crucial protein involved in the formation and clearance of aggresomes, and hence in cell viability in response to misfolded protein stress.

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Section: Ck2 Is a Regulator Of Hdac6 Catalytic Activity And A Bridge mentioning

confidence: 99%

Protein kinase CK2 regulates the formation and clearance of aggresomes in response to stress

Watabe

Nakaki

2011

Journal of Cell Science

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“…General protein degradation and turnover Many (including ↓) [36] Activation and degradation of polypeptide hormones, FGF [37] chemokines, growth factors and their receptors Plasminogen [38] Prolactin [39,40] Endostatin [41] Osteocalcin [42] Thyroglobulin [43] Insulin [44] Glucagon [45] IL-1 [46] IGFBP [47] Androgen receptor [48] Parathyroid hormone [49] MIP-1 alpha [50] MIP-1 beta [50] SLC [50] Activation of enzymatic precursors Cathepsin B [51,52] Cathepsin L [51,53] Transglutaminase 1 [54] Brain antigen processing Amyloid beta A4 protein [55,56] Tau [57] Tubulin [58] Myelin basic protein [59] Mhtt [60] Apolipoprotein E [61] Alpha-synuclein [62] Degradation of cytoskeletal proteins Neurofilaments [63] Actin [64,65] Myosin [64,66] Tropomyosin [65] Monocyte-mediated fibrinolysis Fibrinogen [67,68] Fibrin [67,68] Regulation of apoptosis Bid [69] Thiredoxin-1 [70] Processing of enzyme activators and inhibitors Prosaposin …”

Section: Biological Function Target Protein Referencementioning

confidence: 99%

Cathepsin D—Many functions of one aspartic protease

Beneš

Větvička

Fusek

2008

Critical Reviews in Oncology/Hematology

540

474

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For years, it has been held that cathepsin D (CD) is involved in rather nonspecific protein degradation in a strongly acidic milieu of lysosomes. Studies with CD knock-out mice revealed that CD is not necessary for embryonal development but it is indispensable for postnatal tissue homeostasis. Mutation that abolishes CD enzymatic activity causes neuronal ceroid lipofuscinosis (NCL) characterized by severe neurodegeneration, developmental regression, visual loss and epilepsy in both animals and humans.In the last decade, however, an increasing number of studies demonstrated that enzymatic function of CD is not restricted solely to acidic milieu of lysosomes with important consequences in regulation of apoptosis. In addition to CD enzymatic activity, it has been shown that apoptosis is also regulated by catalytically inactive mutants of CD which suggests that CD interacts with other important molecules and influences cell signaling.Moreover, procathepsin D, secreted from cancer cells, acts as a mitogen on both cancer and stromal cells and stimulates their pro-invasive and pro-metastatic properties. Numerous studies found that pCD/CD level represents an independent prognostic factor in a variety of cancers and is therefore considered to be a potential target of anti-cancer therapy.Studies dealing with functions of cathepsin D are complicated by the fact that there are several simultaneous forms of CD in a cell -pCD, intermediate enzymatically active CD and mature heavy and light chain CD. It became evident that these forms may differently regulate the above mentioned processes.In this article, we review the possible functions of CD and its various forms in cells and organisms during physiological and pathological conditions.

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“…CK1 has been found to co-localize with pS87 in transgenic mice and in LB-like structures in LBD/PD-diseased brains [75,76], and phosphorylates α-Syn at serine87 as well [26]. Oxidative stress induced by iron is reported to upregulate CK2 that leads to increased phosphorylated α-Syn serine129 with an associated increase in oligomerization and inclusion formation [65]. Smith et al [66] have shown in SH-SY5Ycells that the increase in α-Syn phosphorylation under oxidative stress is mediated by CK2 and correlates with enhancement of inclusion formation.…”

Section: Kinases Involved In α-Synuclein Phosphorylationmentioning

confidence: 99%

“…Serine129 of α-Syn can be phosphorylated by G protein-coupled receptor kinases (GRK1, GRK2, GRK5, and GRK6) [61][62][63], casein kinases 1 and 2 (CK1 and CK2) [26,[64][65][66][67][68][69], and the polo-like kinases (PLKs) [70]. Current studies have shown that, GRKs may also phosphorylate non-receptor substrates, comprising the four members of the Syn family (α-,β-,γ-Syn, and synoretin) in addition to phosphorylating agonist-occupied G protein-coupled receptors (GPCRs) [62].…”

Section: Kinases Involved In α-Synuclein Phosphorylationmentioning

confidence: 99%

Modification of α-Synuclein by Phosphorylation: A Pivotal Event in the Cellular Pathogenesis of Parkinson’s Disease

Ganapathy¹

2017

Protein Phosphorylation

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Post-translational protein modifications play an important role in generating the large diversity of the proteome in comparison to the relatively small number of genes; phosphorylation being the most widespread. Phosphorylation of proteins regulates important molecularswitches for several cellular events and abnormal phosphorylation events are associated in many neurodegenerative diseases. In Parkinson's disease (PD) the main hallmark is the accumulation of cytoplasmic inclusions, Lewy bodies (LBs), consisting of α-synuclein (α-Syn) and ubiquitin. There's another key observation which is increasingly gaining prominence is a modified-form of α-Syn; the phospho α-Syn serine129 (pSyn). The significance of pSyn has gained importance in PD because its accumulation is distinctly enhanced in the diseased condition. The revelation of the involvement of pSyn on α-Syn aggregation, LB formation and neurotoxicity is crucial to understanding the pathogenesis and progression of PD. Since some in vitro and in vivo studies have indicated that pSyn is an early event preceding apoptosis, some important questions now needs to be explored in reference to the physiological functions regulated by phosphorylation, such as dopamine synthesis, vesicle mobilization, regulation of synaptic proteins, and synaptic plasticity. An investigation of the role of enzymes on the phosphorylation and clearance of α-Syn and region-specific susceptibility is required to be determined; to identify viable targets for new therapeutics.

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Oxidative stress‐induced phosphorylation, degradation and aggregation of α‐synuclein are linked to upregulated CK2 and cathepsin D

Cited by 110 publications

References 37 publications

Protein kinase CK2 regulates the formation and clearance of aggresomes in response to stress

Protein kinase CK2 regulates the formation and clearance of aggresomes in response to stress

Cathepsin D—Many functions of one aspartic protease

Modification of α-Synuclein by Phosphorylation: A Pivotal Event in the Cellular Pathogenesis of Parkinson’s Disease

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