CK2 Phosphorylating I2PP2A/SET Mediates Tau Pathology and Cognitive Impairment

Zhang, Qing; Xia, Yiyuan; Wang, Yongjun; Shentu, Yangping; Zeng, Kuan; Mahaman, Yacoubou Abdoul Razak; Huang, Fang; Wu, Mengjuan; Ke, Dan; Wang, Qun; Zhang, Bin; R, Liu; Wang, Jian‐Zhi; Ye, Keqiang; Wang, Xiaochuan

doi:10.3389/fnmol.2018.00146

Cited by 40 publications

(46 citation statements)

References 30 publications

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“…Here, we report a robust accumulation of SET into the cytoplasm of primary and patient-derived AML cells. Several studies in Alzheimer's disease show that CK2 phosphorylates SET on Ser9, in the nuclear localization signal, which is key for SET cytoplasmic localization and inhibition of PP2A, leading to tau hyperphosphorylation 30,31,48 . Here we demonstrate in AML cells that p38β is involved in SET trafficking to the cytosol and PP2A inactivation through the activation of CK2, and that silencing of p38β but not p38α decreases CK2-dependent phosphorylation of SET.…”

Section: Discussionmentioning

confidence: 99%

“…2b, c). It has been reported in Alzheimer's disease models that CK2 phosphorylates Ser9 on SET, leading to its cytoplasmic translocation and inhibition of PP2A, resulting in tau phosphorylation 30,31 . CK2 is overexpressed in most hematological tumors, including AML 32 , and it is a target of p38 signaling 33 .…”

Section: P38β Binds To and Stabilizes Set In Aml Cellsmentioning

confidence: 99%

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A new regulatory mechanism of protein phosphatase 2A activity via SET in acute myeloid leukemia

et al. 2020

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Acute myeloid leukemia (AML) is an aggressive hematologic malignancy. Although novel emerging drugs are available, the overall prognosis remains poor and new therapeutic approaches are required. PP2A phosphatase is a key regulator of cell homeostasis and is recurrently inactivated in AML. The anticancer activity of several PP2A-activating drugs (e.g., FTY720) depends on their interaction with the SET oncoprotein, an endogenous PP2A inhibitor that is overexpressed in 30% of AML cases. Elucidation of SET regulatory mechanisms may therefore provide novel targeted therapies for SET-overexpressing AMLs. Here, we show that upregulation of protein kinase p38β is a common event in AML. We provide evidence that p38β potentiates SET-mediated PP2A inactivation by two mechanisms: facilitating SET cytoplasmic translocation through CK2 phosphorylation, and directly binding to and stabilizing the SET protein. We demonstrate the importance of this new regulatory mechanism in primary AML cells from patients and in zebrafish xenograft models. Accordingly, combination of the CK2 inhibitor CX-4945, which retains SET in the nucleus, and FTY720, which disrupts the SET-PP2A binding in the cytoplasm, significantly reduces the viability and migration of AML cells. In conclusion, we show that the p38β/CK2/SET axis represents a new potential therapeutic pathway in AML patients with SET-dependent PP2A inactivation.

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Section: Discussionmentioning

confidence: 99%

Section: P38β Binds To and Stabilizes Set In Aml Cellsmentioning

confidence: 99%

A new regulatory mechanism of protein phosphatase 2A activity via SET in acute myeloid leukemia

et al. 2020

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“…CKII can phosphorylate tau purified from human brain and neuroblastoma cell line [ 26 , 124 – 126 ]. A study has shown that CKII phosphorylates endogenous specific inhibitor (SET), a potent PP2A inhibitor, inducing tau hyperphosphorylation in neurons and animal models, while inhibition of CKII by TBB eliminated this event [ 127 ]. Thus, inhibition of CKII by TBB might provide a pharmacological interference for treating tauopathy-related disorders.…”

Section: Discussionmentioning

confidence: 99%

Screening of tau protein kinase inhibitors in a tauopathy-relevant cell-based model of tau hyperphosphorylation and oligomerization

et al. 2020

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Tauopathies are a class of neurodegenerative disorders characterized by abnormal deposition of post-translationally modified tau protein in the human brain. Tauopathies are associated with Alzheimer's disease (AD), chronic traumatic encephalopathy (CTE), and other diseases. Hyperphosphorylation increases tau tendency to aggregate and form neurofibrillary tangles (NFT), a pathological hallmark of AD. In this study, okadaic acid (OA, 100 nM), a protein phosphatase 1/2A inhibitor, was treated for 24h in mouse neuroblastoma (N2a) and differentiated rat primary neuronal cortical cell cultures (CTX) to induce tau-hyperphosphorylation and oligomerization as a cell-based tauopathy model. Following the treatments, the effectiveness of different kinase inhibitors was assessed using the tauopathyrelevant tau antibodies through tau-immunoblotting, including the sites: pSer202/pThr205 (AT8), pThr181 (AT270), pSer202 (CP13), pSer396/pSer404 (PHF-1), and pThr231 (RZ3). OA-treated samples induced tau phosphorylation and oligomerization at all tested epitopes, forming a monomeric band (46-67 kDa) and oligomeric bands (170 kDa and 240 kDa). We found that TBB (a casein kinase II inhibitor), AR and LiCl (GSK-3 inhibitors), cyclosporin A (calcineurin inhibitor), and Saracatinib (Fyn kinase inhibitor) caused robust inhibition of OAinduced monomeric and oligomeric p-tau in both N2a and CTX culture. Additionally, a cyclin-dependent kinase 5 inhibitor (Roscovitine) and a calcium chelator (EGTA) showed contrasting results between the two neuronal cultures. This study provides a comprehensive view of potential drug candidates (TBB, CsA, AR, and Saracatinib), and their efficacy against tau hyperphosphorylation and oligomerization processes. These findings warrant further experimentation, possibly including animal models of tauopathies, which may provide a putative Neurotherapy for AD, CTE, and other forms of tauopathy-induced neurodegenerative diseases.

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“…Moreover, it has been reported that CKII can phosphorylate tau purified from human brain and neuroblastoma cell line (18, 83–85). A study has shown that CKII phosphorylates SET, a potent PP2A inhibitor, inducing tau hyperphosphorylation in neurons and animal models, while inhibition of CKII by TBB eliminated this event (86). Thus, inhibition of CKII by TBB might provide a pharmacological interference for treating tauopathy-related disorders.…”

Section: Discussionmentioning

confidence: 99%

Screening of Tau Protein Kinase Inhibitors in a Tauopathy-relevant cell-based model of Tau Hyperphosphorylation and Oligomerization

Yadikar

Torres

Aiello

et al. 2019

Preprint

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26Tauopathies are a class of neurodegenerative disorders characterized by abnormal deposition of 27 post-translationally modified tau protein in the human brain. Tauopathies are associated with 28 Alzheimer's disease (AD), chronic traumatic encephalopathy (CTE), and other diseases. 29Hyperphosphorylation increases tau tendency to aggregate and forms neurofibrillary tangles 30 (NFT), a pathological hallmark of AD. In this study, okadaic acid (OA, 100 nM), a protein 31 phosphatase 1/2A inhibitor, was treated for 24h in mouse neuroblastoma (N2a) and differentiated 32 rat primary neuronal cortical cell cultures (CTX) to induce tau-hyperphosphorylation and 33 oligomerization as a cell-based tauopathy model. Following the treatments, the effectiveness of 34 different kinase inhibitors was assessed using the tauopathy-relevant tau antibodies through tau-35 immunoblotting, including the sites: pSer202/pThr205 (AT8), pThr181 (AT270), pSer202 (CP13), 36 pSer396/pSer404 (PHF-1), and pThr231 (RZ3). OA-treated samples induced tau phosphorylation 37 and oligomerization at all tested epitopes, forming a monomeric band (46-67 kDa) and oligomeric 38 bands (170 kDa and 240 kDa). We found that TBB (a casein kinase II inhibitor), AR and LiCl 39 (GSK-3 inhibitors), cyclosporin A (calcineurin inhibitor), and Saracatinib (Fyn kinase inhibitor) 40 caused robust inhibition of OA-induced monomeric and oligomeric p-tau in both N2a and CTX 41 culture. Additionally, a cyclin-dependent kinase 5 inhibitor (Roscovitine) and a calcium chelator 42 (EGTA) showed conflicting results between the two neuronal cultures.This study provides a 43 comprehensive view of potential drug candidates (TBB, CsA, AR, and Saracatinib), and their 44 efficacy against tau hyperphosphorylation and oligomerization processes. These findings warrant 45 further experimentation, possibly including animal models of tauopathies, which may provide a 46 putative Neurotherapy for AD, CTE, and other forms of tauopathy-induced neurodegenerative 47 diseases.48

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CK2 Phosphorylating I2PP2A/SET Mediates Tau Pathology and Cognitive Impairment

Cited by 40 publications

References 30 publications

A new regulatory mechanism of protein phosphatase 2A activity via SET in acute myeloid leukemia

A new regulatory mechanism of protein phosphatase 2A activity via SET in acute myeloid leukemia

Screening of tau protein kinase inhibitors in a tauopathy-relevant cell-based model of tau hyperphosphorylation and oligomerization

Screening of Tau Protein Kinase Inhibitors in a Tauopathy-relevant cell-based model of Tau Hyperphosphorylation and Oligomerization

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