PPM1A (magnesium-dependent phosphatase 1 A, also known as PP2Cα) is a member of the Ser/Thr protein phosphatase family. Protein phosphatases catalyze the removal of phosphate groups from proteins via hydrolysis, thus opposing the role of protein kinases. The PP2C family is generally considered a negative regulator in the eukaryotic stress response pathway. PPM1A can bind and dephosphorylate various proteins and is therefore involved in the regulation of a wide range of physiological processes. It plays a crucial role in transcriptional regulation, cell proliferation, and apoptosis and has been suggested to be closely related to the occurrence and development of cancers of the lung, bladder, and breast, amongst others. Moreover, it is closely related to certain autoimmune diseases and neurodegenerative diseases. In this review, we provide an insight into currently available knowledge of PPM1A, including its structure, biological function, involvement in signaling pathways, and association with diseases. Lastly, we discuss whether PPM1A could be targeted for therapy of certain human conditions.
KamadaRKudohFItoSTaniIJanairoJIBOmichinskiJGSakaguchiK.Metal-dependent Ser/Thr protein phosphatase PPM family: evolution, structures, diseases and inhibitors. Pharmacol Ther2020;
215:107622
2.
KrzyzosiakASigurdardottirALuhLCarraraMDasISchneiderKBertolottiA.Target-based discovery of an inhibitor of the regulatory phosphatase PPP1R15B. Cell2018;
174:1216–28 e19
3.
LammersTLaviS.Role of type 2C protein phosphatases in growth regulation and in cellular stress signaling. Crit Rev Biochem Mol Biol2007;
42:437–61
4.
DasAKHelpsNRCohenPTBarfordD.Crystal structure of the protein serine/threonine phosphatase 2C at 2.0 a resolution. Embo J1996;
15:6798–809
5.
SinghAPandeyASrivastavaAKTranLSPandeyGK.Plant protein phosphatases 2C: from genomic diversity to functional multiplicity and importance in stress management. Crit Rev Biotechnol2016;
36:1023–35
6.
PanCLiuHDGongZYuXHouXBXieDDZhuXBLiHWTangJYXuYFYuJQZhangLYFangHXiaoKHChenYGWangJYPangQChenWSunJP.Cadmium is a potent inhibitor of PPM phosphatases and targets the M1 binding site. Sci Rep2013;
3:2333
7.
DebnathSKosekDTagadHDDurellSRAppellaDHAcevedoRGrishaevADydaFAppellaEMazurSJ.A trapped human PPM1A-phosphopeptide complex reveals structural features critical for regulation of PPM protein phosphatase activity. J Biol Chem2018;
293:7993–8008
8.
JacksonMDFjeldCCDenuJM.Probing the function of conserved residues in the serine/threonine phosphatase PP2Calpha. Biochemistry2003;
42:8513–21
9.
ChuderlandDDvashiZKaplan-KraicerRBen-MeirDShalgiRLaviS.De novo synthesis of protein phosphatase 1A, magnesium dependent, alpha isoform (PPM1A) during oocyte maturation. Cell Mol Biol Lett2012;
17:433–45
10.
ZhangBZhouZLinHLvXFuJLinPZhuCWangH.Protein phosphatase 1A (PPM1A) is involved in human cytotrophoblast cell invasion and migration. Histochem Cell Biol2009;
132:169–79
11.
ShohatMBen-MeirDLaviS.Protein phosphatase magnesium dependent 1A (PPM1A) plays a role in the differentiation and survival processes of nerve cells. PloS One2012;
7:e32438
12.
KimJHLeeJOhBKimmKKohI.Prediction of phosphorylation sites using SVMs. Bioinformatics2004;
20:3179–84
13.
Lifschitz-MercerBSheininYBen-MeirDBramante-SchreiberLLeider-TrejoLKarbySSmorodinskyNILaviS.Protein phosphatase 2Calpha expression in normal human tissues: an immunohistochemical study. Histochem Cell Biol2001;
116:31–9
14.
LiuYJChernY.AMPK-mediated regulation of neuronal metabolism and function in brain diseases. J Neurogenet2015;
29:50–8
15.
ChenLJiaoZHZhengLSZhangYYXieSTWangZXWuJW.Structural insight into the autoinhibition mechanism of AMP-activated protein kinase. Nature2009;
459:1146–9
16.
DaviesSPHelpsNRCohenPTHardieDG.5'-AMP inhibits dephosphorylation, as well as promoting phosphorylation, of the AMP-activated protein kinase. Studies using bacterially expressed human protein phosphatase-2C alpha and native bovine protein phosphatase-2AC. FEBS Lett1995;
377:421–5
17.
ChidaTAndoMMatsukiTMasuYNagauraYTakano-YamamotoTTamuraSKobayashiT.N-Myristoylation is essential for protein phosphatases PPM1A and PPM1B to dephosphorylate their physiological substrates in cells. Biochem J2013;
449:741–9
18.
HanadaMKobayashiTOhnishiMIkedaSWangHKatsuraKYanagawaYHiragaAKanamaruRTamuraS.Selective suppression of stress-activated protein kinase pathway by protein phosphatase 2C in mammalian cells. FEBS Lett1998;
437:172–6
19.
DvashiZSar ShalomHShohatMBen-MeirDFerberSSatchi-FainaroRAshery-PadanRRosnerMSolomonASLaviS.Protein phosphatase magnesium dependent 1A governs the wound healing-inflammation-angiogenesis cross talk on injury. Am J Pathol2014;
184:2936–50
20.
SchaafKSmithSRDuvergerAWagnerFWolschendorfFWestfallAOKutschOSunJ.Mycobacterium tuberculosis exploits the PPM1A signaling pathway to block host macrophage apoptosis. Sci Rep2017;
7:42101
21.
TakekawaMMaedaTSaitoH.Protein phosphatase 2Calpha inhibits the human stress-responsive p38 and JNK MAPK pathways. Embo J1998;
17:4744–52
22.
ZhouBWangZXZhaoYBrautiganDLZhangZY.The specificity of extracellular signal-regulated kinase 2 dephosphorylation by protein phosphatases. J Biol Chem2002;
277:31818–25
23.
MorganDO.Principles of CDK regulation. Nature1995;
374:131–4
24.
ChengAKaldisPSolomonMJ.Dephosphorylation of human cyclin-dependent kinases by protein phosphatase type 2C alpha and beta 2 isoforms. J Biol Chem2000;
275:34744–9
25.
ChengARossKEKaldisPSolomonMJ.Dephosphorylation of cyclin-dependent kinases by type 2C protein phosphatases. Genes Dev1999;
13:2946–57
26.
WangYDowECLiangYYRamakrishnanRLiuHSungTLLinXRiceAP.Phosphatase PPM1A regulates phosphorylation of thr-186 in the Cdk9 T-loop. J Biol Chem2008;
283:33578–84
27.
BudhirajaSRamakrishnanRRiceAP.Phosphatase PPM1A negatively regulates P-TEFb function in resting CD4(+) T cells and inhibits HIV-1 gene expression. Retrovirology2012;
9:52
28.
VogelsteinBLaneDLevineAJ.Surfing the p53 network. Nature2000;
408:307–10
29.
OfekPBen-MeirDKariv-InbalZOrenMLaviS.Cell cycle regulation and p53 activation by protein phosphatase 2C alpha. J Biol Chem2003;
278:14299–305
30.
BierieBMosesHL.Tumour microenvironment: TGFbeta: the molecular Jekyll and Hyde of cancer. Nat Rev Cancer2006;
6:506–20
31.
LinXDuanXLiangYYSuYWrightonKHLongJHuMDavisCMWangJBrunicardiFCShiYChenYGMengAFengXH.PPM1A functions as a Smad phosphatase to terminate TGFbeta signaling. Cell2006;
125:915–28
32.
WangFWangHSunLNiuCXuJ.TRIM59 inhibits PPM1A through ubiquitination and activates TGF-β/Smad signaling to promote the invasion of ectopic endometrial stromal cells in endometriosis. Am J Physiol Cell Physiol2020;
319:C392–c401
LuXYarbroughWG.Negative regulation of RelA phosphorylation: emerging players and their roles in cancer. Cytokine Growth Factor Rev2015;
26:7–13
36.
SunWYuYDottiGShenTTanXSavoldoBPassAKChuMZhangDLuXFuSLinXYangJ.PPM1A and PPM1B act as IKKbeta phosphatases to terminate TNFalpha-induced IKKbeta-NF-kappaB activation. Cell Signal2009;
21:95–102
37.
TangJGoldschmedingRSamarakoonRHigginsPJ.Protein phosphatase Mg(2+)/Mn(2+) dependent-1A and PTEN deregulation in renal fibrosis: novel mechanisms and co-dependency of expression. Faseb J2020;
34:2641–56
38.
SamarakoonRRehfussAKhakooNSFalkeLLDobberfuhlADHeloSOverstreetJMGoldschmedingRHigginsPJ.Loss of expression of protein phosphatase magnesium-dependent 1A during kidney injury promotes fibrotic maladaptive repair. Faseb J2016;
30:3308–20
39.
ZhouJLanQLiWYangLYouJZhangYMNiW.Tripartite motif protein 52 (TRIM52) promoted fibrosis in LX-2 cells through PPM1A-mediated Smad2/3 pathway. Cell Biol Int2019. DOI: 10.1002/cbin.11206
40.
LeeJELeeJSHwangSH.Microarray for genes associated with signal transduction in diabetic OLETF keratocytes. Korean J Ophthalmol2007;
21:111–9
ChoiJHBanksASEstallJLKajimuraSBoströmPLaznikDRuasJLChalmersMJKameneckaTMBlüherMGriffinPRSpiegelmanBM.Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARgamma by Cdk5. Nature2010;
466:451–6
43.
BanksASMcAllisterFECamporezJPZushinPJJurczakMJLaznik-BogoslavskiDShulmanGIGygiSPSpiegelmanBM.An ERK/Cdk5 axis controls the diabetogenic actions of PPARγ. Nature2015;
517:391–5
44.
KhimKWChoiSSJangHJLeeYHLeeEHyunJMEomHJYoonSChoiJWParkTENamDChoiJH.PPM1A controls diabetic gene programming through directly dephosphorylating PPARγ at Ser273. Cells2020;
9:343
45.
LiZLiuGSunLTengYGuoXJiaJShaJYangXChenDSunQ.PPM1A regulates antiviral signaling by antagonizing TBK1-mediated STING phosphorylation and aggregation. PLoS Pathog2015;
11:e1004783
46.
XiangWZhangQLinXWuSZhouYMengFFanYShenTXiaoMXiaZZouJFengXHXuP.PPM1A silences cytosolic RNA sensing and antiviral defense through direct dephosphorylation of MAVS and TBK1. Sci Adv2016;
2:e1501889
47.
SunJSchaafKDuvergerAWolschendorfFSpeerAWagnerFNiederweisMKutschO.Protein phosphatase, Mg2+/Mn2+-dependent 1A controls the innate antiviral and antibacterial response of macrophages during HIV-1 and Mycobacterium tuberculosis infection. Oncotarget2016;
7:15394–409
GengJFanJOuyangQZhangXZhangXYuJXuZLiQYaoXLiuXZhengJ.Loss of PPM1A expression enhances invasion and the epithelial-to-mesenchymal transition in bladder cancer by activating the TGF-β/Smad signaling pathway. Oncotarget2014;
5:5700–11
50.
HongYGongLYuBDongY.PPM1A suppresses the proliferation and invasiveness of RCC cells via Smad2/3 signaling inhibition. J Receptor Signal Transd Res2021;
41:245–54
51.
MazumdarATahaneyWMReddy BolluLPoageGHillJZhangYMillsGBBrownPH.The phosphatase PPM1A inhibits triple negative breast cancer growth by blocking cell cycle progression. NPJ Breast Cancer2019;
5:22
52.
ZhouYZhaoYGaoYHuWQuYLouNZhuYZhangXYangH.Hepatitis C virus NS3 protein enhances hepatocellular carcinoma cell invasion by promoting PPM1A ubiquitination and degradation. J Exp Clin Cancer Res2017;
36:42
53.
ZhangYTaoRWuSSXuCCWangJLChenJYuYSTangZHChenXHZangGQ.TRIM52 up-regulation in hepatocellular carcinoma cells promotes proliferation, migration and invasion through the ubiquitination of PPM1A. J Exp Clin Cancer Res2018;
37:116
54.
PondugulaSRFlanneryPCApteUBabuJRGeethaTRegeSDChenTAbbottKL.Mg2+/Mn2+-dependent phosphatase 1A is involved in regulating pregnane X receptor-mediated cytochrome p450 3A4 gene expression. Drug Metab Dispos2015;
43:385–91
55.
FanJYangMXOuyangQFuDXuZLiuXMino-KenudsonMGengJTangF.Phosphatase PPM1A is a novel prognostic marker in pancreatic ductal adenocarcinoma. Hum Pathol2016;
55:151–8
56.
KimYGSohnDHZhaoXSokoloveJLindstromTMYooBLeeCKReveilleJDTaurogJDRobinsonWH.Role of protein phosphatase magnesium-dependent 1A and anti-protein phosphatase magnesium-dependent 1A autoantibodies in ankylosing spondylitis. Arthritis Rheumatol2014;
66:2793–803
57.
LeeBSongYSRhodesCGohTSRohJSJeongHParkJLeeHNLeeSGKimSKimMLeeSISohnDHRobinsonWH.Protein phosphatase magnesium-dependent 1A induces inflammation in rheumatoid arthritis. Biochem Biophys Res Commun2020;
522:731–5
58.
MaTChenYVingtdeuxVZhaoHViolletBMarambaudPKlannE.Inhibition of AMP-activated protein kinase signaling alleviates impairments in hippocampal synaptic plasticity induced by amyloid β. J Neurosci2014;
34:12230–8
59.
CoughlanKSMitchemMRHoggMCPrehnJH.Preconditioning" with latrepirdine, an adenosine 5'-monophosphate-activated protein kinase activator, delays amyotrophic lateral sclerosis progression in SOD1(G93A) mice. Neurobiol Aging2015;
36:1140–50
60.
JuTCChenHMChenYCChangCPChangCChernY.AMPK-α1 functions downstream of oxidative stress to mediate neuronal atrophy in Huntington's disease. Biochim Biophys Acta2014;
1842:1668–80
61.
ColinEZalaDLiotGRangoneHBorrell-PagèsMLiXJSaudouFHumbertS.Huntingtin phosphorylation acts as a molecular switch for anterograde/retrograde transport in neurons. Embo J2008;
27:2124–34
62.
WarbySCChanEYMetzlerMGanLSingarajaRRCrockerSFRobertsonHAHaydenMR.Huntingtin phosphorylation on serine 421 is significantly reduced in the striatum and by polyglutamine expansion in vivo. Hum Mol Genet2005;
14:1569–77
63.
MarionSUrsNMPetersonSMSotnikovaTDBeaulieuJMGainetdinovRRCaronMG.Dopamine D2 receptor relies upon PPM/PP2C protein phosphatases to dephosphorylate huntingtin protein. J Biol Chem2014;
289:11715–24
64.
GeldersGBaekelandtVVan der PerrenA.Linking neuroinflammation and neurodegeneration in Parkinson's disease. J Immunol Res2018;
2018:4784268
65.
LinMTBealMF.Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature2006;
443:787–95
66.
ChiHChangHYSangTK.Neuronal cell death mechanisms in major neurodegenerative diseases. Ijms2018;
19:3082
67.
SchwarzSHufnagelBDworakMKlumppSKrieglsteinJ.Protein phosphatase type 2Calpha and 2Cbeta are involved in fatty acid-induced apoptosis of neuronal and endothelial cells. Apoptosis2006;
11:1111–9
68.
TulgrenEDBakerSTRappLGurneyAMGrillB.PPM-1, a PP2Cα/β phosphatase, regulates axon termination and synapse formation in Caenorhabditis elegans. Genetics2011;
189:1297–307
69.
SeidelKMahlkeJSiswantoSKrügerRHeinsenHAuburgerGBouzrouMGrinbergLTWichtHKorfHWden DunnenWRübU.The brainstem pathologies of Parkinson's disease and dementia with lewy bodies. Brain Pathol2015;
25:121–35
70.
ZarowCLynessSAMortimerJAChuiHC.Neuronal loss is greater in the locus coeruleus than nucleus basalis and substantia nigra in Alzheimer and Parkinson diseases. Arch Neurol2003;
60:337–41
71.
AlbericoSLCassellMDNarayananNS.The vulnerable ventral tegmental area in Parkinson's disease. Basal Ganglia2015;
5:51–5
72.
CohenP.The role of protein phosphorylation in human health and disease. The sir Hans Krebs medal lecture. Eur J Biochem2001;
268:5001–10
73.
McCluskeyASimATSakoffJA.Serine-threonine protein phosphatase inhibitors: development of potential therapeutic strategies. J Med Chem2002;
45:1151–75
74.
ZhangMYogeshaSDMayfieldJEGillGNZhangY.Viewing serine/threonine protein phosphatases through the eyes of drug designers. Febs J2013;
280:4739–60
75.
RogersJPBeuscher AEFlajoletMMcAvoyTNairnACOlsonAJGreengardP.Discovery of protein phosphatase 2C inhibitors by virtual screening. J Med Chem2006;
49:1658–67
76.
PereiraJMChevalierCChazeTGianettoQImpensFMatondoMCossartPHamonMA.Infection reveals a modification of SIRT2 critical for chromatin association. Cell Rep2018;
23:1124–37
77.
VogtATamewitzASkokoJSikorskiRPGiulianoKALazoJS.The benzo[c]phenanthridine alkaloid, sanguinarine, is a selective, cell-active inhibitor of mitogen-activated protein kinase phosphatase-1. J Biol Chem2005;
280:19078–86
