PP2C蛋白磷酸酶调控的细胞信号通路研究进展
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摘要
2C类蛋白磷酸酶是蛋白磷酸酶家族的重要成员,可以对丝/苏氨酸残基特异性脱磷酸。近来研究表明,2C类蛋白磷酸酶控制着大量关键的细胞功能,如增殖、细胞周期阻滞、衰老和细胞程序性死亡、凋亡和自噬等,因而在介导机体免疫反应、衰老、神经发育及肿瘤发生发展中发挥重要的生物学作用。总结PP2C基因各亚型参与介导的重要细胞信号通路,如丝裂原活化蛋白激酶(MAPK)、磷脂酰肌醇3-激酶/丝苏氨酸蛋白激酶(PI3K/AKT)、转化生长因子-β(TGF-β)/Smads、核转录因子-κB(NF-κB)及DNA损伤应答通路,以期为阐明上述生理病理过程的分子基础和调控机制提供新的思路。
The protein phosphatase 2C family(PP2C ),belonging the protein phosphatases,is a kind of importantly specific serine/threonine dephosphatase.Recent studies show that PP2C control a lot of critical cellular functions:proliferation,cell cycle arrest,senescence and programmed cell death,apoptosis and autophagy,showing potentially biological role in regulating immune response,aging,neurogenesis and tumorigenesis.Several dominant cellular signaling pathways controlled by PP2C gene subtypes were reviewed in this paper,such as mitogen-activated protein kinase(MAPK),phosphatidylinositol 3-kinase(PI3K)-AKT,transforming growth factorβ(TGF-β)/Smads,transcription factor nuclear factor-κB(NF-κB)and DNA-damage response pathways,which offered new ways to clarify the molecular basis and regular mechanisms for those physiological and pathological processes.
The protein phosphatase 2C family(PP2C ),belonging the protein phosphatases,is a kind of importantly specific serine/threonine dephosphatase.Recent studies show that PP2C control a lot of critical cellular functions:proliferation,cell cycle arrest,senescence and programmed cell death,apoptosis and autophagy,showing potentially biological role in regulating immune response,aging,neurogenesis and tumorigenesis.Several dominant cellular signaling pathways controlled by PP2C gene subtypes were reviewed in this paper,such as mitogen-activated protein kinase(MAPK),phosphatidylinositol 3-kinase(PI3K)-AKT,transforming growth factorβ(TGF-β)/Smads,transcription factor nuclear factor-κB(NF-κB)and DNA-damage response pathways,which offered new ways to clarify the molecular basis and regular mechanisms for those physiological and pathological processes.
引文
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[2] OGHABI BAKHSHAIESH T, MAJIDZADEH-A K,ESMAEILI R.Wip1:A candidate phosphatase for cancer diagnosis and treatment[J].DNA Repair(Amst),2017,54:63-66.
[3] LU X,AN H,JIN R,et al.PPM1Ais a RelA phosphatase with tumor suppressor-like activity[J].Oncogene,2014,33(22):2918-2927.
[4] LIU T,LIU Y,CAO J,et al.ILKAP binding to and dephosphorylating HIF-1αis essential for apoptosis induced by severe hypoxia[J].Cell Physiol Biochem,2018,46(6):2500-2507.
[5] TANG Y,PAN B,ZHOU X,et al.Wip1-dependent modulation of macrophage migration and phagocytosis[J].Redox Biol,2017,13:665-673.
[6] MATHUR A,PANDEY VK,KAKKAR P.PHLPP:aputative cellular target during insulin resistance and type 2diabetes[J].J Endocrinol,2017,233(3):R185-R198.
[7] LIU G,HU X,SUN B,et al.Phosphatase Wip1negatively regulates neutrophil development through p38 MAPKSTAT1[J].Blood,2013,121(3):519-529.
[8] YU Y,LI J,WAN Y,et al.GADD45αinduction by nickel negatively regulates JNKs/p38 activation via promoting PP2Cαexpression[J].PLoS ONE,2013,8(3):e57185.
[9] NEWTON AC,TROTMAN LC.Turning off AKT:PHLPP as a drug target[J].Annu Rev Pharmacol Toxicol,2014,54:537-558.
[10] SUN Y,TIAN H,WANG L.Effects of PTEN on the proliferation and apoptosis of colorectal cancer cells viathe phosphoinositol-3-kinase/Akt pathway[J].Oncol Rep,2015,33(4):1828-1836.
[11] GRZECHNIK AT,NEWTON AC.PHLPPing through history:a decade in the life of PHLPP phosphatases[J].Biochem Soc Trans,2016,44(6):1675-1682.
[12] NITSCHE C,EDDERKAOUI M,MOORE RM,et al.The phosphatase PHLPP1regulates Akt2,promotes pancreatic cancer cell death,and inhibits tumor formation[J].Gastroenterology,2012,142(2):377-387.
[13] HWANG SM,FEIGENSON M,BEGUN DL,et al.Phlpp inhibitors block pain and cartilage degradation associated with osteoarthritis[J].J Orth Res,2018,36(5):1487-1497.
[14] QIN Y,MENG L,FU Y,et al.SNORA74Bgene silencing inhibits gallbladder cancer cells by inducing PHLPP and suppressing Akt/mTOR signaling[J].Oncotarget,2017,8(12):19980-19996.
[15] JANG SW,YANG SJ,SRINIVASAN S,et al.Akt phosphorylates Mstl and prevents its proteolytic activation,blocking FOXO3phosphorylation and nuclear translocation[J].J Biol Chem,2007,282(42):30836-30844.
[16] QIAO M,WANG Y,XU X,et al.Mst1is an interacting protein that mediates PHLPPs′induced apoptosis[J].Mol Cell,2010,38(4):512-523.
[17] KARIN M.Nuclear factor-kappaB in cancer development and progression[J].Nature,2006,441(7092):431-436.
[18] RINKENBAUGH AL,BALDWIN AS.The NF-κB pathway and cancer stem cells[J].Cells,2016,5(2):E12.
[19] CHRISTIAN F,SMITH EL,CARMODY RJ.The Regulation of NF-κB Subunits by Phosphorylation[J].Cells,2016,5(1):12.
[20] SUN W,YU Y,DOTTI G,et al.PPM1Aand PPM1Bact as IKKbeta phosphatases to terminate TNFα-induced IKKbeta-NF-kappaB activation[J].Cell Signal,2009,21(1):95-102.
[21] AGARWAL NK,ZHU X,GAGEA M,et al.PHLPP2suppresses the NF-κB pathway by inactivating IKKβkinase[J].Oncotarget,2014,5(3):815-823.
[22] MIN J,ZASLAVSKY A,FEDELE G,et al.An oncogenetumor suppressor cascade drives metastatic prostate cancer by coordinately activating Ras and nuclear factor-kappaB[J].Nat Med,2010,16(3):286-294.
[23] CHEN LF,GREENE WC.Shaping the nuclear action of NFkappaB[J].Nat Rev Mol Cell Biol,2004,5(5):392-401.
[24] LIU L,DAI Y,CHEN J,et al.Maelstrom promotes hepatocellular carcinoma metastasis by inducing epithelial-mesenchymal transition by way of Akt/GSK-3β/snail signaling[J].Hepatology,2014,59(2):531-543.
[25] SHEN XF,ZHAO Y,JIANG JP,et al.Phosphatase Wip1in immunity:an overview and update[J].Front Immunol,2017,8:8.
[26] LOWE JM,CHA H,YANG Q,et al.Nuclear factor-kappaB(NF-kappaB)is a novel positive transcriptional regulator of the oncogenic Wip1phosphatase[J].J Biol Chem,2010,285(8):5249-5257.
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