プロテインホスファターゼ2A(PP2A)を活性させる16の方法

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PP2Aとアルツハイマー病

 

概要

細胞は、機能を維持するために細胞内をタンパク質のリン酸化と脱リン酸化反応を繰り返している。

リン酸化タンパク質へリン酸基を付加する酵素をプロテインキナーゼ(リン酸化酵素)と呼ぶ。

反対に、リン酸化タンパク質からリン酸基を脱離させる酵素をプロテインホスファターゼ(脱リン酸化酵素)と呼ぶ。

この2つの酵素の働きにより、生体内のリン酸化の活性レベルが調節されている。

プロテインホスファターゼ入門 大西素子研究室 中部大学
セリン/スレオニン ホスファターゼ

セリン/スレオニンを基質とするプロテインホスファターゼをSer/Thrホスファターゼと呼ぶ。

Ser/Thrホスファターゼは、その化学的性質によってPP1、PP2A、PP2B、PP4、PP5、PP6、PP7に分類される。

プロテイン ホスファターゼ2A(PP2A)

PP2AはすべてのSer/Thrホスファターゼの中で最も広い特異性を示し、真核細胞に広く一般的に存在する。

PP2Aは主に代謝調節、シグナル伝達、DNA複製・転写、細胞増殖などの広い細胞機能に関与しており、血液がんの腫瘍抑制因子としても同定されている。

PP2Aの機能低下はパーキンソン病、アルツハイマー病と関連しており、治療標的候補のひとつとして浮上している。

アルツハイマー病

タウホスファターゼPP2A

PP2Aは脳のリン酸化を調節する主要なタウホスファターゼ。(71%を占める)

アルツハイマー病の脳ではPP2Aが半減。特定のタウリン酸化酵素が重要な役割を果たす。

Contributions of Protein Phosphatases PP1, PP2A, PP2B and PP5 to the Regulation of Tau Phosphorylation - PubMed
Abnormal hyperphosphorylation of tau is believed to lead to neurofibrillary degeneration in Alzheimer's disease (AD) and other tauopathies. Recent studies have
PP2A阻害因子の増加

核内I1 PP2A(PP2A阻害因子1)および細胞質I2 PP2A(PP2A阻害因子2)の活性は、アルツハイマー病脳において20%増加する。

Up-Regulation of Inhibitors of Protein Phosphatase-2A in Alzheimer’s Disease
The activity of protein phosphatase-2A (PP2A) is compromised and is believed to be a cause of the abnormal hyperphosphorylation of tau in Alzheimer’s disease (A
I1PP2A Affects Tau Phosphorylation via Association With the Catalytic Subunit of Protein Phosphatase 2A - PubMed
In Alzheimer disease (AD) brain, the level of I (1)(PP2A), a 249-amino acid long endogenous inhibitor of protein phosphatase 2A (PP2A), is increased, the activi
PPP2A阻害因子によるタウのリン酸化

核内I1 PP2Aおよび細胞質I2 PP2A活性はタウの過剰リン酸化を誘導。

I1PP2A Affects Tau Phosphorylation via Association With the Catalytic Subunit of Protein Phosphatase 2A - PubMed
In Alzheimer disease (AD) brain, the level of I (1)(PP2A), a 249-amino acid long endogenous inhibitor of protein phosphatase 2A (PP2A), is increased, the activi
Mechanism of inhibition of PP2A activity and abnormal hyperphosphorylation of tau by I2PP2A/SET
Protein phosphatase-2A (PP2A) activity, which is compromised in Alzheimer disease brain, is regulated by two endogenous inhibitors, one of them being …

PP2Aの機能不全は、タウの過剰リン酸化、アミロイド形成およびシナプス欠損に関連している。

PP2Aの調節因子およびPP2A触媒活性の変化

サブユニットの発現

メチル化および/またはリン酸化

が、アルツハイマー病患者の脳領域で生じていることが報告されている。

Altered Expression Levels of the Protein Phosphatase 2A ABalphaC Enzyme Are Associated With Alzheimer Disease Pathology - PubMed
The formation of amyloid-containing senile plaques and tau-rich neurofibrillary tangles are central events in Alzheimer disease (AD) pathogenesis. Significantly
Phosphoprotein Phosphatase Activities in Alzheimer Disease Brain - PubMed
Microtubule-associated protein tau is known to be hyperphosphorylated in Alzheimer disease brain and this abnormal hyperphosphorylation is associated with an in
Phosphatase Activity Toward Abnormally Phosphorylated Tau: Decrease in Alzheimer Disease Brain - PubMed
Microtubule-associated protein tau is abnormally hyperphosphorylated and aggregated in affected neurons of Alzheimer disease brain. This hyperphosphorylated tau
PP2A mRNA Expression Is Quantitatively Decreased in Alzheimer's Disease Hippocampus - PubMed
Since abnormal tau phosphorylation may play a role in neurofibrillary tangle (NFT) formation in aging and Alzheimer's disease (AD), we probed the distribution a

PP2A酵素の変調は、アルツハイマー病に関与するその他の多くのセリン / スレオニンホスファターゼの活性にも影響する。

その他の疾患

PP2A関連経路は、アルツハイマー病だけではなく多くの疾患に関与している。

PP2A活性の喪失は癌、神経変性疾患の両方の病理学的なメカニズムを含みうる。

Small-Molecule Activators of Protein Phosphatase 2A for the Treatment of Castration-Resistant Prostate Cancer - PubMed
Primary prostate cancer is generally treatable by androgen deprivation therapy, however, later recurrences of castrate-resistant prostate cancer (CRPC) that are

急性骨髄性白血病

Development of Novel PP2A Activators for Use in the Treatment of Acute Myeloid Leukaemia - PubMed
AAL(S), the chiral deoxy analog of the FDA approved drug FTY720, has been shown to inhibit proliferation and apoptosis in several cancer cell lines. It has been

慢性閉塞性肺疾患(COPD)

Protein Phosphatase 2A Regulates Innate Immune and Proteolytic Responses to Cigarette Smoke Exposure in the Lung - PubMed
Protein phosphatase 2A (PP2A) is the primary serine-threonine phosphatase of eukaryotic cells, and changes in its activity have been linked to neoplastic and ne

心疾患

Cardiac Function Is Regulated by B56α-mediated Targeting of Protein Phosphatase 2A (PP2A) to Contractile Relevant Substrates - PubMed
Dephosphorylation of important myocardial proteins is regulated by protein phosphatase 2A (PP2A), representing a heterotrimer that is comprised of catalytic, sc
対照的な役割を持つ糖尿病におけるPP2A

インスリンシグナル伝達が正常に機能している場合にはおいてインスリンの分泌はPP2Aの不活性化をもたらす。グルコースホメオスタシスが機能を果たすには、PP2Aのダウンレギュレーションを必要とする。

しかし、2型糖尿病患者ではインスリン分泌によるPP2Aの減少は見いだせなかった。

cAMP Counter-Regulates Insulin-Mediated Protein phosphatase-2A Inactivation in Rat Skeletal Muscle Cells - PubMed
In this study, we examined the mechanism of recently reported inactivation of protein phosphatase-2A (PP-2A) by insulin (Srinivasan, M., and Begum, N. (1994) J.
Effect of Insulin on Protein Phosphatase 2A Expression in Muscle in Type 2 Diabetes - PubMed
Down-regulation of PP2A-C alpha expression by insulin in skeletal muscle seems to be associated with a normal insulin action on glucose storage, glucose and lip

PP2Aの構造

Serine/Threonine Phosphatases: Mechanism through Structure
The reversible phosphorylation of proteins is accomplished by opposing activities of kinases and phosphatases. Relatively few protein serine/threonine…

「pp2a」の画像検索結果

A:足場サブユニット、B:調節サブユニット C:触媒サブユニット

Regulation of PP2A by Sphingolipid Metabolism and Signaling
Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase that is a primary regulator of cellular proliferation through targeting of proliferative kinases

PP2Aを構成する触媒ユニットC末端のメチル化により、ホロ酵素の形成が促進されある。

ホロ酵素が形成されたメチル化PP2Aはタウタンパク質に対して高い活性をもつようになる。

PP2Aはヒトの脳のタウの脱リン酸化を71%を媒介する。

 

画像、イラストなどを保持する外部ファイル。オブジェクト名はnihms733535f4.jpgです。

All roads lead to PP2A: Exploiting the therapeutic potential of this phosphatase
Protein phosphatase 2A is a serine/threonine phosphatase involved in the regulation of many cellular processes. A confirmed tumor suppressor protein, PP2A is ge
PP2Aのメチル化

ロイシンカルボキシルメチルトランスフェラーゼ1(LCMT-1)

PP2Aの脱メチル化

プロテインホスファターゼメチルエステラーゼ1(PME-1)

 

PP2Aの作用メカニズム

「pp2a」の画像検索結果

Figure 2: Therapeutic targets in the neurotrophin pathway.Levels of...
Download scientific diagram | Therapeutic targets in the neurotrophin pathway.Levels of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) a
GSK-3βはPP2Aの発現を減少させる
Glycogen Synthase kinase-3β Regulates Tyr307 Phosphorylation of Protein phosphatase-2A via Protein Tyrosine Phosphatase 1B but Not Src - PubMed
GSK-3β (glycogen synthase kinase-3β), a crucial tau kinase, negatively regulates PP2A (protein phosphatase 2A), the most active tau phosphatase that is suppress
Glycogen Synthase kinase-3β Regulates leucine-309 Demethylation of Protein phosphatase-2A via PPMT1 and PME-1 - PubMed
Protein phosphatase-2A (PP2A) activity is significantly suppressed in Alzheimer's disease. We have reported that glycogen synthase kinase-3β (GSK-3β) inhibits P

PP2Aの活性

ハーブ

フォルスコリン

フォルスコリン(coleonol)

Biguanide Metformin Acts on Tau Phosphorylation via mTOR/protein Phosphatase 2A (PP2A) Signaling - PubMed
Hyperphosphorylated tau plays an important role in the formation of neurofibrillary tangles in brains of patients with Alzheimer's disease (AD) and related tauo
Forskolin: Unique Diterpene Activator of Adenylate Cyclase in Membranes and in Intact Cells - PubMed
The diterpene, forskolin activates adenylate cyclase in rat cerebral cortical membranes in a rapid and reversible manner. Activation is not dependent on exoge
PP2A Impaired Activity Is a Common Event in Acute Myeloid Leukemia and Its Activation by Forskolin Has a Potent Anti-Leukemic Effect - PubMed
Protein phosphatase 2A (PP2A) is a human tumor suppressor that inhibits cellular transformation by regulating the activity of several signaling proteins critica
A Novel cAMP-stimulated Pathway in Protein Phosphatase 2A Activation - PubMed
Elevated cAMP in NRK-52E and L6 cells causes a marked reduction in the phosphorylation of numerous phosphoproteins, as detected initially with phosphoserine-spe
Protein Phosphatase 2A (PP2A), a Drugable Tumor Suppressor in Ph1(+) Leukemias - PubMed
Protein phosphatase-2A (PP2A) is one of the major cellular serine-threonine phosphatases and is involved in the regulation of cell homeostasis through the negat
EGCG(緑茶カテキン)
Sealing Effects of (-)-Epigallocatechin Gallate on Protein Kinase C and Protein Phosphatase 2A - PubMed
(-)-Epigallocatechin gallate (EGCG) was reported to inhibit protein kinase C (PKC) activation by 12-O-tetradecanoylphorbol-13-acetate (TPA), and inhibit interac
カルノシン酸(ローズマリー)

ローズマリーから単離されたカルノシン酸によるPP2Aの調節効果 in vitro

Carnosic Acid Modulates Akt/IKK/NF-κB Signaling by PP2A and Induces Intrinsic and Extrinsic Pathway Mediated Apoptosis in Human Prostate Carcinoma PC-3 Cells - PubMed
This study investigates the efficacy of carnosic acid (CA), a polyphenolic diterpene, isolated from the plant rosemary (Rosemarinus officinalis), on androgen-in

栄養化合物

ビタミンE(α-トコフェロール)
alpha-Tocopheryl Succinate and Derivatives Mediate the Transcriptional Repression of Androgen Receptor in Prostate Cancer Cells by Targeting the PP2A-JNK-Sp1-signaling Axis - PubMed
As part of our effort to understand the mechanism underlying alpha-tocopheryl succinate -mediated antitumor effects, we investigated the signaling pathway by wh
PMC, a Potent Hydrophilic α-tocopherol Derivative, Inhibits NF-κB Activation via PP2A but Not IκBα-dependent Signals in Vascular Smooth Muscle Cells - PubMed
The hydrophilic α-tocopherol derivative, 2,2,5,7,8-pentamethyl-6-hydroxychromane (PMC), is a promising alternative to vitamin E in clinical applications. Critic
ベタイン、SAM、ビタミンB

葉酸、B12の低値によるホモシステイン濃度の上昇はPP2Aのメチル化を妨害

Protein phosphatase 2A dysfunction in Alzheimer’s disease
Protein phosphatase 2A (PP2A) is a large family of enzymes that account for the majority of brain Ser/Thr phosphatase activity. While PP2A enzymes collectively
パルミチン酸

パルミチン酸が、セラミド依存性PP2A活性化を介して、内皮細胞におけるAMPKおよび内皮酸化窒素合成酵素のリン酸化を阻害する。

PubMed

ホルモン

メラトニン

メラトニンは、PP2A負リン酸化を部分的に逆転させ、酸化ストレスのマーカーであるマロンジアルデヒドレベルを低下させた。in vivo

PubMed
プロゲステロン
PubMed

PP2A活性 薬剤

メトホルミン
Biguanide Metformin Acts on Tau Phosphorylation via mTOR/protein Phosphatase 2A (PP2A) Signaling - PubMed
Hyperphosphorylated tau plays an important role in the formation of neurofibrillary tangles in brains of patients with Alzheimer's disease (AD) and related tauo
メマンチン

メマンチンは、ラットの海馬PP2A活性を増加させ、タウリン酸化を減少させる。

PubMed
Memantine Attenuates Alzheimer’s Disease-Like Pathology and Cognitive Impairment
Deficiency of protein phosphatase-2A is a key event in Alzheimer’s disease. An endogenous inhibitor of protein phosphatase-2A, inhibitor-1, I , which inhibits
トログリタゾン(PPARγアゴニスト)
PubMed
PubMed
1,8-ナフチリジン(コリンエステラーゼ阻害剤)
PubMed
ジチオレチオン
PubMed
タウロリジン
PubMed
4-ヒドロキシノネナール
PubMed
PubMed
フェノチアジン
PubMed
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