ArticleThe Journal of biological chemistry2014
Cytoplasmic retention of protein phosphatase 2A inhibitor 2 (I2PP2A) induces Alzheimer-like abnormal hyperphosphorylation of Tau.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 62 citations in OpenAlex.
- Potential links between PCOS/PMOS and Alzheimer disease and related dementias.Journal of the Endocrine Society · 2026Review
- The CD97-PPM1G axis dampens antiviral immunity by dephosphorylating IRF7 in type I interferon pathway.PLoS pathogens · 2026Article
- Oxidative Stress: Pathological Driver in Chronic Neurodegenerative Diseases.Antioxidants (Basel, Switzerland) · 2025Review
- The next decade of SET: from an oncoprotein to beyond.Journal of molecular cell biology · 2024Review
- Cancer progression by the okadaic acid class of tumor promoters and endogenous protein inhibitors of PP2A, SET and CIP2A.Journal of cancer research and clinical oncology · 2023Review
- Thirty years of SET/TAF1β/I2PP2A: from the identification of the biological functions to its implications in cancer and Alzheimer's disease.Bioscience reports · 2022Review
- Biomarker Candidates for Alzheimer's Disease Unraveled through In Silico Differential Gene Expression Analysis.Diagnostics (Basel, Switzerland) · 2022Article
- PP2A is activated by cytochromeComputational and structural biotechnology journal · 2022Article
- Network Analysis Identifies Sex-Specific Gene Expression Changes in Blood of Amyotrophic Lateral Sclerosis Patients.International journal of molecular sciences · 2021Article
- Prostaglandin A1 Decreases the Phosphorylation of Tau by Activating Protein Phosphatase 2A via a Michael Addition Mechanism at Cysteine 377.Molecular neurobiology · 2021Article
- Zinc Finger Proteins in Neuro-Related Diseases Progression.Frontiers in neuroscience · 2021Review
- MHC Phosphopeptides: Promising Targets for Immunotherapy of Cancer and Other Chronic Diseases.Molecular & cellular proteomics : MCP · 2021Review
- Discovering the genes mediating the interactions between chronic respiratory diseases in the human interactome.Nature communications · 2020Article
- Revisiting the intersection of amyloid, pathologically modified tau and iron in Alzheimer's disease from a ferroptosis perspective.Progress in neurobiology · 2020Review
- Transmembrane Peptides as a New Strategy to Inhibit Neuraminidase-1 Activation.Frontiers in cell and developmental biology · 2020Article
- SE translation mRNA overexpression: a potential prognostic predictor in breast cancer.Translational cancer research · 2019Article
- PP2ACα of Alveolar Macrophages Is a Novel Protective Factor for LPS-Induced Acute Respiratory Distress Syndrome.Inflammation · 2019Article
- To be or not to be: PP2A as a dual player in CNS functions, its role in neurodegeneration, and its interaction with brain insulin signaling.Cellular and molecular life sciences : CMLS · 2019Review
- Human neuroblastoma SH-SY5Y cells treated with okadaic acid express phosphorylated high molecular weight tau-immunoreactive protein species.Journal of neuroscience methods · 2019Article
- Fibroblast growth factor 21 ameliorates neurodegeneration in rat and cellular models of Alzheimer's disease.Redox biology · 2019Article
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7 authors at 1 institution in 1 country.
Funding
Abstract
Abnormal hyperphosphorylation of Tau leads to the formation of neurofibrillary tangles, a hallmark of Alzheimer disease (AD), and related tauopathies. The phosphorylation of Tau is regulated by protein phosphatase 2A (PP2A), which in turn is modulated by endogenous inhibitor 2 (I2 (PP2A)). In AD brain, I2 (PP2A) is translocated from neuronal nucleus to cytoplasm, where it inhibits PP2A activity and promotes abnormal phosphorylation of Tau. Here we describe the identification of a potential nuclear localization signal (NLS) in the C-terminal region of I2 (PP2A) containing a conserved basic motif, (179)RKR(181), which is sufficient for directing its nuclear localization. The current study further presents an inducible cell model (Tet-Off system) of AD-type abnormal hyperphosphorylation of Tau by expressing I2 (PP2A) in which the NLS was inactivated by (179)RKR(181) → AAA along with (168)KR(169) → AA mutations. In this model, the mutant NLS (mNLS)-I2 (PP2A) (I2 (PP2A)AA-AAA) was retained in the cell cytoplasm, where it physically interacted with PP2A and inhibited its activity. Inhibition of PP2A was associated with the abnormal hyperphosphorylation of Tau, which resulted in microtubule network instability and neurite outgrowth impairment. Expression of mNLS-I2 (PP2A) activated CAMKII and GSK-3β, which are Tau kinases regulated by PP2A. The immunoprecipitation experiments showed the direct interaction of I2 (PP2A) with PP2A and GSK-3β but not with CAMKII. Thus, the cell model provides insights into the nature of the potential NLS and the mechanistic relationship between I2 (PP2A)-induced inhibition of PP2A and hyperphosphorylation of Tau that can be utilized to develop drugs preventing Tau pathology.
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