CIP2A Causes Tau/APP Phosphorylation, Synaptopathy, and Memory Deficits in Alzheimer’s Disease

Shentu, Yang Ping; Huo, Yuda; Feng, Xingdong; Gilbert, James P.; Zhang, Qing; Liuyang, Zhen Yu; Wang, Xiu Lian; Wang, Guan; Zhou, Huan; Wang, Xiao Chuan; Wang, Jian Zhi; Lü, You; Westermarck, Jukka; Man, Heng Ye; Liu, Rong

doi:10.1016/j.celrep.2018.06.009

Cited by 73 publications

(66 citation statements)

References 45 publications

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“…Treatment with this apoE-mimetic peptide suppressed microglial activation and secretion of inflammatory mediators (e.g., TNF-α and IL-6 proteins) in primary microglial cultures and microglial cell lines: ApoE is an antagonist of SET protein (Christensen et al 2011b). CIP2A-mediated PP2A inhibition drives tau/APP hyperphosphorylation and increases APPβ-cleavage and Aβ production (plaques) between neurons (Shentu et al 2018). Both the enhancing endogenous PP2A activity and the antagonizing SET and CIP2A reduce levels of phosphorylated kinases and inflammatory response with TNF-α, IL-1 and IL-6.…”

Section: Discussionmentioning

confidence: 99%

The concept of the okadaic acid class of tumor promoters is revived in endogenous protein inhibitors of protein phosphatase 2A, SET and CIP2A, in human cancers

Fujiki

Sueoka

Watanabe

et al. 2018

J Cancer Res Clin Oncol

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PurposeThe okadaic acid class of tumor promoters, which are inhibitors of protein phosphatases 1 and 2A (PP1 and PP2A), induced tumor promotion in mouse skin, rat glandular stomach, and rat liver. Endogenous protein inhibitors of PP2A, SET and CIP2A, were up-regulated in various human cancers, so it is vital to review the essential mechanisms of tumor promotion by the okadaic acid class compounds, together with cancer progression by SET and CIP2A in humans.Results and discussionThe first part of this review introduces the okadaic acid class compounds and the mechanism of tumor promotion: (1) inhibition of PP1 and PP2A activities of the okadaic acid class compounds; (2) some topics of tumor promotion; (3) TNF-α gene expression as a central mediator in tumor promotion; (4) exposure to the okadaic acid class of tumor promoters in relation to human cancer. The second part emphasizes the overexpression of SET and CIP2A in cancer progression, and the anticancer activity of SET antagonists as follows: (5) isolation and characterization of SET; (6) isolation and characterization of CIP2A; (7) progression of leukemia with SET; (8) progression of breast cancer with SET and CIP2A; (9) progression of lung cancer with SET; (10) anti-carcinogenic effects of SET antagonists OP449 and FTY720; and also (11) TNF-α-inducing protein of Helicobacter pylori, which is a clinical example of the okadaic acid pathway.ConclusionsThe overexpression of endogenous protein inhibitors of PP2A, SET and CIP2A, is tightly linked to the progression of various human cancers, as well as Alzheimer’s disease.

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Section: Discussionmentioning

confidence: 99%

The concept of the okadaic acid class of tumor promoters is revived in endogenous protein inhibitors of protein phosphatase 2A, SET and CIP2A, in human cancers

Fujiki

Sueoka

Watanabe

et al. 2018

J Cancer Res Clin Oncol

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“…Beta spectrin has been identified as an integral component of beta-amyloid plaques in Alzheimer’s disease (AD) and spectrin breakdown products (SBDPs) have been implicated as potential biomarkers for neurodegenerative diseases including AD [49], [50]. In a recent study of AD, CIP2A was found to be overexpressed and associated with tau hyperphosphorylation, mis-localization and AD-related cellular pathology [14]. In mice, overexpression of CIP2A in the brain induced AD-like cognitive deficits [14].…”

Section: Discussionmentioning

confidence: 99%

“…In a recent study of AD, CIP2A was found to be overexpressed and associated with tau hyperphosphorylation, mis-localization and AD-related cellular pathology [14]. In mice, overexpression of CIP2A in the brain induced AD-like cognitive deficits [14]. Future studies may determine whether CIP2A interaction with beta-spectrin modulates protein aggregation in AD pathology.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, inhibition of either CIP2A dimerization or B56 α / γ expression destabilizes CIP2A in cancer cells [13]. In Alzheimer’s disease (AD), enhanced expression of CIP2A in AD brains and neurons results in PP2A inhibition and tau protein hyperphosphorylation, which leads to abnormal tau localization with memory deficits and other pathological conditions [14].…”

Section: Introductionmentioning

confidence: 99%

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Protein Interactome of the Cancerous Inhibitor of Protein Phosphatase 2A (CIP2A) in Th17 Cells

Khan

Välikangas

Khan

et al. 2019

Preprint

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29Cancerous inhibitor of protein phosphatase 2A (CIP2A) is involved in immune 30 response, cancer progression, and in Alzheimer´s disease. However, an 31 understanding of the mechanistic basis of its function in this wide spectrum of 32 physiological and pathological processes is limited due to its poorly characterized 33 interaction networks. Here we present the first systematic characterization of the 34 CIP2A interactome by affinity-purification mass spectrometry combined with validation 35 by selected reaction monitoring targeted mass spectrometry (SRM-MS) analysis in 36 Th17 cells. In addition to the known regulatory subunit of protein phosphatase PP2A, 37 the catalytic subunit of protein PP2A was found to be interacting with CIP2A. 38 Furthermore, the regulatory (PPP1R18, and PPP1R12A) and catalytic (PPP1CA) 39 subunits of phosphatase PP1 were identified among the top novel CIP2A interactors. 40 Evaluation of the ontologies associated with the proteins in this interactome revealed 41 that they were linked with RNA metabolic processing and splicing, protein traffic, 42 cytoskeleton regulation and ubiquitin-mediated protein degradation processes. Taken 43 together, this network of protein-protein interactions will be important for 44 understanding and further exploring the biological processes and mechanisms 45 regulated by CIP2A both in physiological and pathological conditions.46 Monitoring (SRM) targeted mass spectrometry, confocal microscopy, Pathway 48 analysis.49 Highlights: 50 § The first characterisation of the CIP2A interactome in Th17 cells. 51 3 § Key interactions were validated by targeted SRM-MS proteomics, western blot 52 and confocal microscopy. 53 § Pathway analysis of the interactome revealed interrelationships with proteins 54 across a broad range of processes, in particular associated with mRNA 55 processing. 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72PP2A is a recognized tumor suppressor that imparts crucial functions in regulating cell 73 proliferation, differentiation, and apoptosis [1] - [7] . Accordingly, down regulation of 74 PP2A has been observed as a feature in many cancers. Cancerous Inhibitor of PP2A 75 (CIP2A) was first characterized as an endogenous inhibitor of protein phosphatase 2A 76 (PP2A) in cancer cells [8] . Previous studies have shown that many of the known 77 actions of CIP2A are mediated through inhibition of PP2A [9] , [10] . Overexpression 78 of CIP2A has been associated with the poor prognosis in several human malignancies, 79 and CIP2A has thus been seen as a potential therapeutic target for cancer therapy [8] 80 , [11] , [12] . CIP2A supports the activity of many critical onco-proteins (Akt, MYC, 81 E2F1) and promotes malignancy in most cancer types via PP2A inhibition [8] . 82 Structurally, CIP2A forms a homodimer and this dimerization promotes its interaction 83 with the PP2A regulatory subunits B56a and B56g [13] . Interestingly, inhibition of 84 either CIP2A dimerization or B56a/g expression destabilizes CIP2A in cancer cells ...

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“…The upregulation of APP T668 phosphorylation could also be a consequence of the deactivation of protein phosphatase (PP) in vivo. AD patients have an increased level of cancerous inhibitor of protein phosphatase 2A (CIP2A) compared with that of age-matched controls [79]. CIP2A inhibits the activity of PP2A and promotes APP T668 phosphorylation, triggering the β-cleavage of APP, Aβ production, and tau hyperphosphorylation [79].…”

Section: App Phosphorylationmentioning

confidence: 99%

Phosphorylation Signaling in APP Processing in Alzheimer’s Disease

Zhang

Chen

Lee

2019

IJMS

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The abnormal accumulation of amyloid-β (Aβ) in the central nervous system is a hallmark of Alzheimer's disease (AD). The regulation of the processing of the single-transmembrane amyloid precursor protein (APP) plays an important role in the generation of Aβ in the brain. The phosphorylation of APP and key enzymes involved in the proteolytic processing of APP has been demonstrated to be critical for modulating the generation of Aβ by either altering the subcellular localization of APP or changing the enzymatic activities of the secretases responsible for APP processing. In addition, the phosphorylation may also have an impact on the physiological function of these proteins. In this review, we summarize the kinases and signaling pathways that may participate in regulating the phosphorylation of APP and secretases and how this further affects the function and processing of APP and Aβ pathology. We also discuss the potential of approaches that modulate these phosphorylation-signaling pathways or kinases as interventions for AD pathology.

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CIP2A Causes Tau/APP Phosphorylation, Synaptopathy, and Memory Deficits in Alzheimer’s Disease

Cited by 73 publications

References 45 publications

The concept of the okadaic acid class of tumor promoters is revived in endogenous protein inhibitors of protein phosphatase 2A, SET and CIP2A, in human cancers

The concept of the okadaic acid class of tumor promoters is revived in endogenous protein inhibitors of protein phosphatase 2A, SET and CIP2A, in human cancers

Protein Interactome of the Cancerous Inhibitor of Protein Phosphatase 2A (CIP2A) in Th17 Cells

Phosphorylation Signaling in APP Processing in Alzheimer’s Disease

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