Progress on cell signaling pathways regulated by PP2C protein phosphatases

QI Yang; XU Weiheng; ZHANG Junping; SONG Hongtao

doi:10.3969/j.issn.1006-0111.2018.05.001

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Article Navigation > Journal of Pharmaceutical Practice and Service > 2018 > 36(5): 385-388,456

QI Yang, XU Weiheng, ZHANG Junping, SONG Hongtao. Progress on cell signaling pathways regulated by PP2C protein phosphatases[J]. Journal of Pharmaceutical Practice and Service, 2018, 36(5): 385-388,456. doi: 10.3969/j.issn.1006-0111.2018.05.001

Citation:

QI Yang, XU Weiheng, ZHANG Junping, SONG Hongtao. Progress on cell signaling pathways regulated by PP2C protein phosphatases[J]. Journal of Pharmaceutical Practice and Service, 2018, 36(5): 385-388,456. doi: 10.3969/j.issn.1006-0111.2018.05.001

Progress on cell signaling pathways regulated by PP2C protein phosphatases

doi: 10.3969/j.issn.1006-0111.2018.05.001

1.
Department of Pharmacy, Fuzhou General Hospital, Fuzhou 350025, China
2.
School of Pharmacy, Second Military Medical University, Shanghai 200433, China

Received Date: 2017-11-23
Rev Recd Date: 2018-07-01

Abstract

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 factor β(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.
- PP2C protein phosphatases,
- cell signaling pathways,
- MAPK,
- PI3K-AKT,
- TGF-β/Smads,
- NF-κB,
- DNA-damage response

References

[1]	TONG Y, QUIRION R, SHEN SH. Cloning and characterization of a novel mammalian PP2C isozyme[J]. J Biol Chem, 1998, 273(52):35282-35290.
[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. PPM1A is 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-1α is 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:a putative cellular target during insulin resistance and type 2 diabetes[J]. J Endocrinol, 2017, 233(3):R185-R198.
[7]	LIU G, HU X, SUN B, et al. Phosphatase Wip1 negatively regulates neutrophil development through p38 MAPK-STAT1[J]. Blood, 2013, 121(3):519-529.
[8]	YU Y, LI J, WAN Y, et al. GADD45α induction by nickel negatively regulates JNKs/p38 activation via promoting PP2Cα expression[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 via the 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 PHLPP1 regulates 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. SNORA74B gene 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 FOXO3 phosphorylation and nuclear translocation[J]. J Biol Chem, 2007, 282(42):30836-30844.
[16]	QIAO M, WANG Y, XU X, et al. Mst1 is 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. PPM1A and PPM1B act 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. PHLPP2 suppresses the NF-κB pathway by inactivating IKKβ kinase[J]. Oncotarget, 2014, 5(3):815-823.
[22]	MIN J, ZASLAVSKY A, FEDELE G, et al. An oncogene-tumor 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 NF-kappaB[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 Wip1 in 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 Wip1 phosphatase[J]. J Biol Chem, 2010, 285(8):5249-5257.
[27]	LIN X, DUAN X, LIANG YY, et al. PPM1A functions as a Smad phosphatase to terminate TGFβ signaling[J]. Cell, 2016, 165(2):498.
[28]	DAI F, SHEN T, LI Z, et al. PPM1A dephosphorylates RanBP3 to enable efficient nuclear export of Smad2 and Smad3[J]. EMBO Rep, 2011, 12(11):1175-1181.
[29]	WANG L, WANG X, CHEN J, et al. Activation of protein serine/threonine phosphatase PP2Cα efficiently prevents liver fibrosis[J]. PLoS ONE, 2010, 5(12):e14230.
[30]	MIYAZONO K. Transforming growth factor-beta signaling in epithelial-mesenchymal transition and progression of cancer[J]. Phys Biol Sci, 2009, 85(8):314-323.
[31]	GENG J, FAN J, OUYANG Q, et al. Loss of PPM1A expression enhances invasion and the epithelial-to-mesenchymal transition in bladder cancer by activating the TGF-β/Smad signaling pathway[J]. Oncotarget, 2014, 5(14):5700-5711.
[32]	FURGASON JM, BAHASSI el M. Targeting DNA repair mechanisms in cancer[J]. Pharmacol Ther, 2013, 137(3):298-308.
[33]	LEEM J, KIM JS, OH JS. WIPL phosphatase suppresses the DNA damage response during G2/prophase arrest in mouse oocytes[J]. Biol Reprod, 2018(Epub).
[34]	JAISWAL H, BENADA J, MVLLERS E, et al. ATM/Wip1 activities at chromatin control Plk1 re-activation to determine G2 checkpoint duration[J]. EMBO J, 2017, 36(14):2161-2176.
[35]	WANG ZP, TIAN Y, LIN J. Role of wild-type p53-induced phosphatase 1 in cancer[J]. Oncol Lett, 2017, 14(4):3893-3898.
[36]	OLIVA-TRASTOY M, BERTHONAUD V, CHEVALIER A, et al. The Wip1 phosphatase (PPM1D) antagonizes activation of the Chk2 tumour suppressor kinase[J]. Oncogene, 2006, 26(10):1449-1458.
[37]	SLUSS HK, ARMATA H, GALLANT J, et al. Phosphorylation of serine 18 regulates distinct p53 functions in mice[J]. Mol Cell Biol, 2004, 24(3):976-984.
[38]	GOLOUDINA AR, KOCHETKOVA EY, POSPELOVA TV, et al. Wip1 phosphatase:between p53 and MAPK kinases pathways[J]. Oncotarget, 2016, 7(21):31563-31571.

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通讯作者: 陈斌, bchen63@163.com

1.
沈阳化工大学材料科学与工程学院沈阳 110142

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Progress on cell signaling pathways regulated by PP2C protein phosphatases

1. Department of Pharmacy, Fuzhou General Hospital, Fuzhou 350025, China

2. School of Pharmacy, Second Military Medical University, Shanghai 200433, China

Received Date: 2017-11-23

Rev Recd Date: 2018-07-01

Key words:

Abstract: 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 factor β(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.

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Reference (38)

[1]	TONG Y, QUIRION R, SHEN SH. Cloning and characterization of a novel mammalian PP2C isozyme[J]. J Biol Chem, 1998, 273(52):35282-35290.
[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. PPM1A is 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-1α is 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:a putative cellular target during insulin resistance and type 2 diabetes[J]. J Endocrinol, 2017, 233(3):R185-R198.
[7]	LIU G, HU X, SUN B, et al. Phosphatase Wip1 negatively regulates neutrophil development through p38 MAPK-STAT1[J]. Blood, 2013, 121(3):519-529.
[8]	YU Y, LI J, WAN Y, et al. GADD45α induction by nickel negatively regulates JNKs/p38 activation via promoting PP2Cα expression[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 via the 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 PHLPP1 regulates 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. SNORA74B gene 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 FOXO3 phosphorylation and nuclear translocation[J]. J Biol Chem, 2007, 282(42):30836-30844.
[16]	QIAO M, WANG Y, XU X, et al. Mst1 is 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. PPM1A and PPM1B act 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. PHLPP2 suppresses the NF-κB pathway by inactivating IKKβ kinase[J]. Oncotarget, 2014, 5(3):815-823.
[22]	MIN J, ZASLAVSKY A, FEDELE G, et al. An oncogene-tumor 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 NF-kappaB[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 Wip1 in 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 Wip1 phosphatase[J]. J Biol Chem, 2010, 285(8):5249-5257.
[27]	LIN X, DUAN X, LIANG YY, et al. PPM1A functions as a Smad phosphatase to terminate TGFβ signaling[J]. Cell, 2016, 165(2):498.
[28]	DAI F, SHEN T, LI Z, et al. PPM1A dephosphorylates RanBP3 to enable efficient nuclear export of Smad2 and Smad3[J]. EMBO Rep, 2011, 12(11):1175-1181.
[29]	WANG L, WANG X, CHEN J, et al. Activation of protein serine/threonine phosphatase PP2Cα efficiently prevents liver fibrosis[J]. PLoS ONE, 2010, 5(12):e14230.
[30]	MIYAZONO K. Transforming growth factor-beta signaling in epithelial-mesenchymal transition and progression of cancer[J]. Phys Biol Sci, 2009, 85(8):314-323.
[31]	GENG J, FAN J, OUYANG Q, et al. Loss of PPM1A expression enhances invasion and the epithelial-to-mesenchymal transition in bladder cancer by activating the TGF-β/Smad signaling pathway[J]. Oncotarget, 2014, 5(14):5700-5711.
[32]	FURGASON JM, BAHASSI el M. Targeting DNA repair mechanisms in cancer[J]. Pharmacol Ther, 2013, 137(3):298-308.
[33]	LEEM J, KIM JS, OH JS. WIPL phosphatase suppresses the DNA damage response during G2/prophase arrest in mouse oocytes[J]. Biol Reprod, 2018(Epub).
[34]	JAISWAL H, BENADA J, MVLLERS E, et al. ATM/Wip1 activities at chromatin control Plk1 re-activation to determine G2 checkpoint duration[J]. EMBO J, 2017, 36(14):2161-2176.
[35]	WANG ZP, TIAN Y, LIN J. Role of wild-type p53-induced phosphatase 1 in cancer[J]. Oncol Lett, 2017, 14(4):3893-3898.
[36]	OLIVA-TRASTOY M, BERTHONAUD V, CHEVALIER A, et al. The Wip1 phosphatase (PPM1D) antagonizes activation of the Chk2 tumour suppressor kinase[J]. Oncogene, 2006, 26(10):1449-1458.
[37]	SLUSS HK, ARMATA H, GALLANT J, et al. Phosphorylation of serine 18 regulates distinct p53 functions in mice[J]. Mol Cell Biol, 2004, 24(3):976-984.
[38]	GOLOUDINA AR, KOCHETKOVA EY, POSPELOVA TV, et al. Wip1 phosphatase:between p53 and MAPK kinases pathways[J]. Oncotarget, 2016, 7(21):31563-31571.

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Progress on cell signaling pathways regulated by PP2C protein phosphatases

doi: 10.3969/j.issn.1006-0111.2018.05.001

Abstract

References

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通讯作者: 陈斌, bchen63@163.com

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