Skip to main content

Advertisement

SpringerLink
Log in

The impact of phosphatases on proliferative and survival signaling in cancer

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

The dynamic and stringent coordination of kinase and phosphatase activity controls a myriad of physiologic processes. Aberrations that disrupt the balance of this interplay represent the basis of numerous diseases. For a variety of reasons, early work in this area portrayed kinases as the dominant actors in these signaling events with phosphatases playing a secondary role. In oncology, these efforts led to breakthroughs that have dramatically altered the course of certain diseases and directed vast resources toward the development of additional kinase-targeted therapies. Yet, more recent scientific efforts have demonstrated a prominent and sometimes driving role for phosphatases across numerous malignancies. This maturation of the phosphatase field has brought with it the promise of further therapeutic advances in the field of oncology. In this review, we discuss the role of phosphatases in the regulation of cellular proliferation and survival signaling using the examples of the MAPK and PI3K/AKT pathways, c-Myc and the apoptosis machinery. Emphasis is placed on instances where these signaling networks are perturbed by dysregulation of specific phosphatases to favor growth and persistence of human cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

AKT:

AKT serine/threonine kinase

AML:

Acute myeloid leukemia

APAF-1:

Apoptotic peptidase-activating factor-1

B-ALL:

B-cell lymphoblastic leukemia/lymphoma

BH3:

Bcl-2 homology 3

CDK:

Cyclin-dependent kinase

DISC:

Death-inducing signaling complex

DUSP:

Dual-specificity phosphatase

ERK:

Extracellular signal-regulated kinase

FAP-1:

Fas-associated phosphatase-1

Fas:

Fas cell surface death receptor

FasL:

Fas ligand

FCP:

F-cell production

GAP:

GTPase-activating protein

GEF:

Guanine nucleotide exchange factor

GPCR:

G protein-coupled receptor

GSK:

Glycogen synthase kinase

JNK:

c-Jun NH2 terminal kinase

KSR:

Kinase suppressor of Ras

MAPK:

Mitogen-activated protein kinase

MEK:

Mitogen-activated protein kinase kinase

MEKK:

Mitogen-activated protein kinase kinase kinase

MKP:

Mitogen-activated protein kinase phosphatase

MNK:

Mitogen-activated protein kinase interacting serine/threonine kinase

MOMP:

Mitochondrial outer membrane permeabilization

MTA:

Microtubule-targeting agent

MYC:

MYC proto-oncogene, basic helix-loop-helix transcription factor

NF-κB:

Nuclear factor kappa B

OA:

Okadaic acid

PH:

Pleckstrin homology

PHLPP:

Pleckstrin homology domain leucine-rich repeat protein phosphatase

PI3K:

Phosphoinositol-3-kinase

PIP2:

Phosphatidylinositol-4,5-biphosphate

PIP3:

Phosphatidylinositol-3,4,5-triphosphate

PIP:

Phosphatidylinositol phosphate

PKC:

Protein kinase C

PP1:

Protein phosphatase 1

PP2A:

Protein phosphatase 2A

PPM:

Metal-dependent protein phosphatase

PPP:

Phosphoprotein phosphatase

PSP:

Protein serine/threonine phosphatase

PTEN:

Phosphatase and tensin homolog deleted on chromosome 10

PTM:

Post-translational modification

PTP:

Protein tyrosine phosphatase

RTK:

Receptor tyrosine kinase

SCP:

Small carboxy-terminal domain phosphatase

SH2:

Src homology 2

SOS:

Son of sevenless protein

t-Bid:

Truncated Bid

References

  1. Lemmon MA, Freed DM, Schlessinger J, Kiyatkin A (2016) The dark side of cell signaling: positive roles for negative regulators. Cell 164(6):1172–1184. https://doi.org/10.1016/j.cell.2016.02.047

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Gross S, Rahal R, Stransky N, Lengauer C, Hoeflich KP (2015) Targeting cancer with kinase inhibitors. J Clin Invest 125(5):1780–1789. https://doi.org/10.1172/JCI76094

    Article  PubMed  PubMed Central  Google Scholar 

  3. Stebbing J, Lit LC, Zhang H, Darrington RS, Melaiu O, Rudraraju B, Giamas G (2014) The regulatory roles of phosphatases in cancer. Oncogene 33(8):939–953. https://doi.org/10.1038/onc.2013.80

    Article  PubMed  CAS  Google Scholar 

  4. Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner SH, Giovanella BC, Ittmann M, Tycko B, Hibshoosh H, Wigler MH, Parsons R (1997) PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275(5308):1943–1947

    Article  PubMed  CAS  Google Scholar 

  5. Steck PA, Pershouse MA, Jasser SA, Yung WK, Lin H, Ligon AH, Langford LA, Baumgard ML, Hattier T, Davis T, Frye C, Hu R, Swedlund B, Teng DH, Tavtigian SV (1997) Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet 15(4):356–362. https://doi.org/10.1038/ng0497-356

    Article  PubMed  CAS  Google Scholar 

  6. Stanford SM, Bottini N (2017) Targeting tyrosine phosphatases: time to end the stigma. Trends Pharmacol Sci 38(6):524–540. https://doi.org/10.1016/j.tips.2017.03.004

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M (2006) Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 127(3):635–648. https://doi.org/10.1016/j.cell.2006.09.026

    Article  PubMed  CAS  Google Scholar 

  8. Frankson R, Yu ZH, Bai Y, Li Q, Zhang RY, Zhang ZY (2017) Therapeutic targeting of oncogenic tyrosine phosphatases. Cancer Res 77(21):5701–5705. https://doi.org/10.1158/0008-5472.CAN-17-1510

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Zhang M, Yogesha SD, Mayfield JE, Gill GN, Zhang Y (2013) Viewing serine/threonine protein phosphatases through the eyes of drug designers. FEBS J 280(19):4739–4760. https://doi.org/10.1111/febs.12481

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Tonks NK (2013) Protein tyrosine phosphatases–from housekeeping enzymes to master regulators of signal transduction. FEBS J 280(2):346–378. https://doi.org/10.1111/febs.12077

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Alonso A, Sasin J, Bottini N, Friedberg I, Friedberg I, Osterman A, Godzik A, Hunter T, Dixon J, Mustelin T (2004) Protein tyrosine phosphatases in the human genome. Cell 117(6):699–711. https://doi.org/10.1016/j.cell.2004.05.018

    Article  PubMed  CAS  Google Scholar 

  12. Alonso A, Pulido R (2016) The extended human PTPome: a growing tyrosine phosphatase family. FEBS J 283(8):1404–1429. https://doi.org/10.1111/febs.13600

    Article  PubMed  CAS  Google Scholar 

  13. Elson A (2017) Stepping out of the shadows: oncogenic and tumor-promoting protein tyrosine phosphatases. Int J Biochem Cell Biol. https://doi.org/10.1016/j.biocel.2017.09.013

    Article  PubMed  Google Scholar 

  14. Meeusen B, Janssens V (2017) Tumor suppressive protein phosphatases in human cancer: emerging targets for therapeutic intervention and tumor stratification. Int J Biochem Cell Biol. https://doi.org/10.1016/j.biocel.2017.10.002

    Article  PubMed  Google Scholar 

  15. Sangodkar J, Farrington CC, McClinch K, Galsky MD, Kastrinsky DB, Narla G (2016) All roads lead to PP2A: exploiting the therapeutic potential of this phosphatase. FEBS J 283(6):1004–1024. https://doi.org/10.1111/febs.13573

    Article  PubMed  CAS  Google Scholar 

  16. Ruvolo PP (2016) The broken “Off” switch in cancer signaling: PP2A as a regulator of tumorigenesis, drug resistance, and immune surveillance. BBA Clin 6:87–99. https://doi.org/10.1016/j.bbacli.2016.08.002

    Article  PubMed  PubMed Central  Google Scholar 

  17. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100(1):57–70

    Article  PubMed  CAS  Google Scholar 

  18. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674. https://doi.org/10.1016/j.cell.2011.02.013

    Article  PubMed  CAS  Google Scholar 

  19. Hollander MC, Blumenthal GM, Dennis PA (2011) PTEN loss in the continuum of common cancers, rare syndromes and mouse models. Nat Rev Cancer 11(4):289–301. https://doi.org/10.1038/nrc3037

    Article  PubMed  CAS  Google Scholar 

  20. Bentires-Alj M, Paez JG, David FS, Keilhack H, Halmos B, Naoki K, Maris JM, Richardson A, Bardelli A, Sugarbaker DJ, Richards WG, Du J, Girard L, Minna JD, Loh ML, Fisher DE, Velculescu VE, Vogelstein B, Meyerson M, Sellers WR, Neel BG (2004) Activating mutations of the noonan syndrome-associated SHP2/PTPN11 gene in human solid tumors and adult acute myelogenous leukemia. Cancer Res 64(24):8816–8820. https://doi.org/10.1158/0008-5472.CAN-04-1923

    Article  PubMed  CAS  Google Scholar 

  21. Tartaglia M, Niemeyer CM, Fragale A, Song X, Buechner J, Jung A, Hahlen K, Hasle H, Licht JD, Gelb BD (2003) Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nat Genet 34(2):148–150. https://doi.org/10.1038/ng1156

    Article  PubMed  CAS  Google Scholar 

  22. Engelman JA, Luo J, Cantley LC (2006) The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 7(8):606–619. https://doi.org/10.1038/nrg1879

    Article  PubMed  CAS  Google Scholar 

  23. Vanhaesebroeck B, Guillermet-Guibert J, Graupera M, Bilanges B (2010) The emerging mechanisms of isoform-specific PI3K signalling. Nat Rev Mol Cell Biol 11(5):329–341. https://doi.org/10.1038/nrm2882

    Article  PubMed  CAS  Google Scholar 

  24. Luo J, Manning BD, Cantley LC (2003) Targeting the PI3K-Akt pathway in human cancer: rationale and promise. Cancer Cell 4(4):257–262

    Article  PubMed  CAS  Google Scholar 

  25. Engelman JA (2009) Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer 9(8):550–562. https://doi.org/10.1038/nrc2664

    Article  PubMed  CAS  Google Scholar 

  26. Robbins HL, Hague A (2015) The PI3K/Akt pathway in tumors of endocrine tissues. Front Endocrinol (Lausanne) 6:188. https://doi.org/10.3389/fendo.2015.00188

    Article  Google Scholar 

  27. Fruman DA, Chiu H, Hopkins BD, Bagrodia S, Cantley LC, Abraham RT (2017) The PI3K pathway in human disease. Cell 170(4):605–635. https://doi.org/10.1016/j.cell.2017.07.029

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  28. Zehir A, Benayed R, Shah RH, Syed A, Middha S, Kim HR, Srinivasan P, Gao J, Chakravarty D, Devlin SM, Hellmann MD, Barron DA, Schram AM, Hameed M, Dogan S, Ross DS, Hechtman JF, DeLair DF, Yao J, Mandelker DL, Cheng DT, Chandramohan R, Mohanty AS, Ptashkin RN, Jayakumaran G, Prasad M, Syed MH, Rema AB, Liu ZY, Nafa K, Borsu L, Sadowska J, Casanova J, Bacares R, Kiecka IJ, Razumova A, Son JB, Stewart L, Baldi T, Mullaney KA, Al-Ahmadie H, Vakiani E, Abeshouse AA, Penson AV, Jonsson P, Camacho N, Chang MT, Won HH, Gross BE, Kundra R, Heins ZJ, Chen HW, Phillips S, Zhang H, Wang J, Ochoa A, Wills J, Eubank M, Thomas SB, Gardos SM, Reales DN, Galle J, Durany R, Cambria R, Abida W, Cercek A, Feldman DR, Gounder MM, Hakimi AA, Harding JJ, Iyer G, Janjigian YY, Jordan EJ, Kelly CM, Lowery MA, Morris LGT, Omuro AM, Raj N, Razavi P, Shoushtari AN, Shukla N, Soumerai TE, Varghese AM, Yaeger R, Coleman J, Bochner B, Riely GJ, Saltz LB, Scher HI, Sabbatini PJ, Robson ME, Klimstra DS, Taylor BS, Baselga J, Schultz N, Hyman DM, Arcila ME, Solit DB, Ladanyi M, Berger MF (2017) Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med 23(6):703–713. https://doi.org/10.1038/nm.4333

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Maehama T, Dixon JE (1998) The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem 273(22):13375–13378

    Article  PubMed  CAS  Google Scholar 

  30. Bigner SH, Mark J, Mahaley MS, Bigner DD (1984) Patterns of the early, gross chromosomal changes in malignant human gliomas. Hereditas 101(1):103–113

    Article  PubMed  CAS  Google Scholar 

  31. Liaw D, Marsh DJ, Li J, Dahia PL, Wang SI, Zheng Z, Bose S, Call KM, Tsou HC, Peacocke M, Eng C, Parsons R (1997) Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet 16(1):64–67. https://doi.org/10.1038/ng0597-64

    Article  PubMed  CAS  Google Scholar 

  32. Shojaee S, Chan LN, Buchner M, Cazzaniga V, Cosgun KN, Geng H, Qiu YH, von Minden MD, Ernst T, Hochhaus A, Cazzaniga G, Melnick A, Kornblau SM, Graeber TG, Wu H, Jumaa H, Muschen M (2016) PTEN opposes negative selection and enables oncogenic transformation of pre-B cells. Nat Med 22(4):379–387. https://doi.org/10.1038/nm.4062

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Grzechnik AT, Newton AC (2016) PHLPPing through history: a decade in the life of PHLPP phosphatases. Biochem Soc Trans 44(6):1675–1682. https://doi.org/10.1042/BST20160170

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Gao T, Furnari F, Newton AC (2005) PHLPP: a phosphatase that directly dephosphorylates Akt, promotes apoptosis, and suppresses tumor growth. Mol Cell 18(1):13–24. https://doi.org/10.1016/j.molcel.2005.03.008

    Article  PubMed  CAS  Google Scholar 

  35. Brognard J, Sierecki E, Gao T, Newton AC (2007) PHLPP and a second isoform, PHLPP2, differentially attenuate the amplitude of Akt signaling by regulating distinct Akt isoforms. Mol Cell 25(6):917–931. https://doi.org/10.1016/j.molcel.2007.02.017

    Article  PubMed  CAS  Google Scholar 

  36. Gao T, Brognard J, Newton AC (2008) The phosphatase PHLPP controls the cellular levels of protein kinase C. J Biol Chem 283(10):6300–6311. https://doi.org/10.1074/jbc.M707319200

    Article  PubMed  CAS  Google Scholar 

  37. Liu J, Stevens PD, Li X, Schmidt MD, Gao T (2011) PHLPP-mediated dephosphorylation of S6K1 inhibits protein translation and cell growth. Mol Cell Biol 31(24):4917–4927. https://doi.org/10.1128/MCB.05799-11

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Chen H, Zhang K, Wu G, Song D, Chen K, Yang H (2015) Low expression of PHLPP1 in sacral chordoma and its association with poor prognosis. Int J Clin Exp Pathol 8(11):14741–14748

    PubMed  PubMed Central  CAS  Google Scholar 

  39. Goel A, Arnold CN, Niedzwiecki D, Chang DK, Ricciardiello L, Carethers JM, Dowell JM, Wasserman L, Compton C, Mayer RJ, Bertagnolli MM, Boland CR (2003) Characterization of sporadic colon cancer by patterns of genomic instability. Cancer Res 63(7):1608–1614

    PubMed  CAS  Google Scholar 

  40. Johnson-Pais TL, Nellissery MJ, Ammerman DG, Pathmanathan D, Bhatia P, Buller CL, Leach RJ, Hansen MF (2003) Determination of a minimal region of loss of heterozygosity on chromosome 18q21.33 in osteosarcoma. Int J Cancer 105(2):285–288. https://doi.org/10.1002/ijc.11070

    Article  PubMed  CAS  Google Scholar 

  41. Nitsche C, Edderkaoui M, Moore RM, Eibl G, Kasahara N, Treger J, Grippo PJ, Mayerle J, Lerch MM, Gukovskaya AS (2012) The phosphatase PHLPP1 regulates Akt2, promotes pancreatic cancer cell death, and inhibits tumor formation. Gastroenterology 142(2):377–387, e371–e375. https://doi.org/10.1053/j.gastro.2011.10.026

  42. Rakha EA, Green AR, Powe DG, Roylance R, Ellis IO (2006) Chromosome 16 tumor-suppressor genes in breast cancer. Genes Chromosomes Cancer 45(6):527–535. https://doi.org/10.1002/gcc.20318

    Article  PubMed  CAS  Google Scholar 

  43. Teng DC, Sun J, An YQ, Hu ZH, Liu P, Ma YC, Han B, Shi Y (2016) Role of PHLPP1 in inflammation response: its loss contributes to gliomas development and progression. Int Immunopharmacol 34:229–234. https://doi.org/10.1016/j.intimp.2016.02.034

    Article  PubMed  CAS  Google Scholar 

  44. Andjelkovic M, Jakubowicz T, Cron P, Ming XF, Han JW, Hemmings BA (1996) Activation and phosphorylation of a pleckstrin homology domain containing protein kinase (RAC-PK/PKB) promoted by serum and protein phosphatase inhibitors. Proc Natl Acad Sci USA 93(12):5699–5704

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Chen D, Fucini RV, Olson AL, Hemmings BA, Pessin JE (1999) Osmotic shock inhibits insulin signaling by maintaining Akt/protein kinase B in an inactive dephosphorylated state. Mol Cell Biol 19(7):4684–4694

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Ivaska J, Nissinen L, Immonen N, Eriksson JE, Kahari VM, Heino J (2002) Integrin alpha 2 beta 1 promotes activation of protein phosphatase 2A and dephosphorylation of Akt and glycogen synthase kinase 3 beta. Mol Cell Biol 22(5):1352–1359

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Meier R, Thelen M, Hemmings BA (1998) Inactivation and dephosphorylation of protein kinase Balpha (PKBalpha) promoted by hyperosmotic stress. EMBO J 17(24):7294–7303. https://doi.org/10.1093/emboj/17.24.7294

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Resjo S, Goransson O, Harndahl L, Zolnierowicz S, Manganiello V, Degerman E (2002) Protein phosphatase 2A is the main phosphatase involved in the regulation of protein kinase B in rat adipocytes. Cell Signal 14(3):231–238

    Article  PubMed  CAS  Google Scholar 

  49. Kuo YC, Huang KY, Yang CH, Yang YS, Lee WY, Chiang CW (2008) Regulation of phosphorylation of Thr-308 of Akt, cell proliferation, and survival by the B55alpha regulatory subunit targeting of the protein phosphatase 2A holoenzyme to Akt. J Biol Chem 283(4):1882–1892. https://doi.org/10.1074/jbc.M709585200

    Article  PubMed  CAS  Google Scholar 

  50. Padmanabhan S, Mukhopadhyay A, Narasimhan SD, Tesz G, Czech MP, Tissenbaum HA (2009) A PP2A regulatory subunit regulates C. elegans insulin/IGF-1 signaling by modulating AKT-1 phosphorylation. Cell 136 (5):939–951. https://doi.org/10.1016/j.cell.2009.01.025

  51. Chen W, Possemato R, Campbell KT, Plattner CA, Pallas DC, Hahn WC (2004) Identification of specific PP2A complexes involved in human cell transformation. Cancer Cell 5(2):127–136

    Article  PubMed  CAS  Google Scholar 

  52. Ruvolo PP, Ruvolo VR, Jacamo R, Burks JK, Zeng Z, Duvvuri SR, Zhou L, Qiu Y, Coombes KR, Zhang N, Yoo SY, Pan R, Hail N Jr, Konopleva M, Calin G, Kornblau SM (1843) Andreeff M (2014) The protein phosphatase 2A regulatory subunit B55alpha is a modulator of signaling and microRNA expression in acute myeloid leukemia cells. Biochim Biophys Acta 9:1969–1977. https://doi.org/10.1016/j.bbamcr.2014.05.006

    Article  CAS  Google Scholar 

  53. Shouse G, de Necochea-Campion R, Mirshahidi S, Liu X, Chen CS (2016) Novel B55alpha-PP2A mutations in AML promote AKT T308 phosphorylation and sensitivity to AKT inhibitor-induced growth arrest. Oncotarget 7(38):61081–61092. https://doi.org/10.18632/oncotarget.11209

    Article  PubMed  PubMed Central  Google Scholar 

  54. Curtis C, Shah SP, Chin SF, Turashvili G, Rueda OM, Dunning MJ, Speed D, Lynch AG, Samarajiwa S, Yuan Y, Graf S, Ha G, Haffari G, Bashashati A, Russell R, McKinney S, Group M, Langerod A, Green A, Provenzano E, Wishart G, Pinder S, Watson P, Markowetz F, Murphy L, Ellis I, Purushotham A, Borresen-Dale AL, Brenton JD, Tavare S, Caldas C, Aparicio S (2012) The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature 486 (7403):346–352. https://doi.org/10.1038/nature10983

  55. Liu W, Xie CC, Zhu Y, Li T, Sun J, Cheng Y, Ewing CM, Dalrymple S, Turner AR, Sun J, Isaacs JT, Chang BL, Zheng SL, Isaacs WB, Xu J (2008) Homozygous deletions and recurrent amplifications implicate new genes involved in prostate cancer. Neoplasia 10(8):897–907

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Mosca L, Musto P, Todoerti K, Barbieri M, Agnelli L, Fabris S, Tuana G, Lionetti M, Bonaparte E, Sirchia SM, Grieco V, Bianchino G, D’Auria F, Statuto T, Mazzoccoli C, De Luca L, Petrucci MT, Morabito F, Offidani M, Di Raimondo F, Falcone A, Caravita T, Omede P, Boccadoro M, Palumbo A, Neri A (2013) Genome-wide analysis of primary plasma cell leukemia identifies recurrent imbalances associated with changes in transcriptional profiles. Am J Hematol 88(1):16–23. https://doi.org/10.1002/ajh.23339

    Article  PubMed  CAS  Google Scholar 

  57. Downward J (2003) Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer 3(1):11–22. https://doi.org/10.1038/nrc969

    Article  PubMed  CAS  Google Scholar 

  58. Herrero A, Matallanas D, Kolch W (2016) The spatiotemporal regulation of RAS signalling. Biochem Soc Trans 44(5):1517–1522. https://doi.org/10.1042/BST20160127

    Article  PubMed  CAS  Google Scholar 

  59. Li X, Stevens PD, Liu J, Yang H, Wang W, Wang C, Zeng Z, Schmidt MD, Yang M, Lee EY, Gao T (2014) PHLPP is a negative regulator of RAF1, which reduces colorectal cancer cell motility and prevents tumor progression in mice. Gastroenterology 146 (5):1301–1312, e1301–e1310. https://doi.org/10.1053/j.gastro.2014.02.003

  60. Gagne-Sansfacon J, Coulombe G, Langlois MJ, Langlois A, Paquet M, Carrier J, Feng GS, Qu CK, Rivard N (2016) SHP-2 phosphatase contributes to KRAS-driven intestinal oncogenesis but prevents colitis-associated cancer development. Oncotarget 7(40):65676–65695. https://doi.org/10.18632/oncotarget.11601

    Article  PubMed  PubMed Central  Google Scholar 

  61. Adams DG, Coffee RL Jr, Zhang H, Pelech S, Strack S, Wadzinski BE (2005) Positive regulation of Raf1-MEK1/2-ERK1/2 signaling by protein serine/threonine phosphatase 2A holoenzymes. J Biol Chem 280(52):42644–42654. https://doi.org/10.1074/jbc.M502464200

    Article  PubMed  CAS  Google Scholar 

  62. Ory S, Zhou M, Conrads TP, Veenstra TD, Morrison DK (2003) Protein phosphatase 2A positively regulates RAS signaling by dephosphorylating KSR1 and Raf-1 on critical 14-3-3 binding sites. Curr Biol 13(16):1356–1364

    Article  PubMed  CAS  Google Scholar 

  63. Hein AL, Seshacharyulu P, Rachagani S, Sheinin YM, Ouellette MM, Ponnusamy MP, Mumby MC, Batra SK, Yan Y (2016) PR55alpha subunit of protein phosphatase 2A supports the tumorigenic and metastatic potential of pancreatic cancer cells by sustaining hyperactive oncogenic signaling. Cancer Res 76(8):2243–2253. https://doi.org/10.1158/0008-5472.CAN-15-2119

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Shen S, Yue H, Li Y, Qin J, Li K, Liu Y, Wang J (2014) Upregulation of miR-136 in human non-small cell lung cancer cells promotes Erk1/2 activation by targeting PPP2R2A. Tumour Biol 35(1):631–640. https://doi.org/10.1007/s13277-013-1087-2

    Article  PubMed  CAS  Google Scholar 

  65. Haagenson KK, Wu GS (2010) Mitogen activated protein kinase phosphatases and cancer. Cancer Biol Ther 9(5):337–340

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Nunes-Xavier C, Roma-Mateo C, Rios P, Tarrega C, Cejudo-Marin R, Tabernero L, Pulido R (2011) Dual-specificity MAP kinase phosphatases as targets of cancer treatment. Anticancer Agents Med Chem 11(1):109–132

    Article  PubMed  CAS  Google Scholar 

  67. Calvisi DF, Pinna F, Meloni F, Ladu S, Pellegrino R, Sini M, Daino L, Simile MM, De Miglio MR, Virdis P, Frau M, Tomasi ML, Seddaiu MA, Muroni MR, Feo F, Pascale RM (2008) Dual-specificity phosphatase 1 ubiquitination in extracellular signal-regulated kinase-mediated control of growth in human hepatocellular carcinoma. Cancer Res 68(11):4192–4200. https://doi.org/10.1158/0008-5472.CAN-07-6157

    Article  PubMed  CAS  Google Scholar 

  68. Denkert C, Schmitt WD, Berger S, Reles A, Pest S, Siegert A, Lichtenegger W, Dietel M, Hauptmann S (2002) Expression of mitogen-activated protein kinase phosphatase-1 (MKP-1) in primary human ovarian carcinoma. Int J Cancer 102(5):507–513. https://doi.org/10.1002/ijc.10746

    Article  PubMed  CAS  Google Scholar 

  69. Loda M, Capodieci P, Mishra R, Yao H, Corless C, Grigioni W, Wang Y, Magi-Galluzzi C, Stork PJ (1996) Expression of mitogen-activated protein kinase phosphatase-1 in the early phases of human epithelial carcinogenesis. Am J Pathol 149(5):1553–1564

    PubMed  PubMed Central  CAS  Google Scholar 

  70. Magi-Galluzzi C, Mishra R, Fiorentino M, Montironi R, Yao H, Capodieci P, Wishnow K, Kaplan I, Stork PJ, Loda M (1997) Mitogen-activated protein kinase phosphatase 1 is overexpressed in prostate cancers and is inversely related to apoptosis. Lab Invest 76(1):37–51

    PubMed  CAS  Google Scholar 

  71. Manzano RG, Montuenga LM, Dayton M, Dent P, Kinoshita I, Vicent S, Gardner GJ, Nguyen P, Choi YH, Trepel J, Auersperg N, Birrer MJ (2002) CL100 expression is down-regulated in advanced epithelial ovarian cancer and its re-expression decreases its malignant potential. Oncogene 21(28):4435–4447. https://doi.org/10.1038/sj.onc.1205542

    Article  PubMed  CAS  Google Scholar 

  72. Rauhala HE, Porkka KP, Tolonen TT, Martikainen PM, Tammela TL, Visakorpi T (2005) Dual-specificity phosphatase 1 and serum/glucocorticoid-regulated kinase are downregulated in prostate cancer. Int J Cancer 117(5):738–745. https://doi.org/10.1002/ijc.21270

    Article  PubMed  CAS  Google Scholar 

  73. Shen J, Zhou S, Shi L, Liu X, Lin H, Yu H, Xiaoliang Tang J, Yu T, Cai X (2017) DUSP1 inhibits cell proliferation, metastasis and invasion and angiogenesis in gallbladder cancer. Oncotarget 8(7):12133–12144. https://doi.org/10.18632/oncotarget.14815

    Article  PubMed  PubMed Central  Google Scholar 

  74. Yokoyama A, KaRASaki H, Urushibara N, Nomoto K, Imai Y, Nakamura K, Mizuno Y, Ogawa K, Kikuchi K (1997) The characteristic gene expressions of MAPK phosphatases 1 and 2 in hepatocarcinogenesis, rat ascites hepatoma cells, and regenerating rat liver. Biochem Biophys Res Commun 239(3):746–751. https://doi.org/10.1006/bbrc.1997.7547

    Article  PubMed  CAS  Google Scholar 

  75. Boutros T, Chevet E, Metrakos P (2008) Mitogen-activated protein (MAP) kinase/MAP kinase phosphatase regulation: roles in cell growth, death, and cancer. Pharmacol Rev 60(3):261–310. https://doi.org/10.1124/pr.107.00106

    Article  PubMed  CAS  Google Scholar 

  76. Wu GS (2007) Role of mitogen-activated protein kinase phosphatases (MKPs) in cancer. Cancer Metastasis Rev 26(3–4):579–585. https://doi.org/10.1007/s10555-007-9079-6

    Article  PubMed  CAS  Google Scholar 

  77. Britson JS, Barton F, Balko JM, Black EP (2009) Deregulation of DUSP activity in EGFR-mutant lung cancer cell lines contributes to sustained ERK1/2 signaling. Biochem Biophys Res Commun 390(3):849–854. https://doi.org/10.1016/j.bbrc.2009.10.061

    Article  PubMed  CAS  Google Scholar 

  78. Chitale D, Gong Y, Taylor BS, Broderick S, Brennan C, Somwar R, Golas B, Wang L, Motoi N, Szoke J, Reinersman JM, Major J, Sander C, Seshan VE, Zakowski MF, Rusch V, Pao W, Gerald W, Ladanyi M (2009) An integrated genomic analysis of lung cancer reveals loss of DUSP4 in EGFR-mutant tumors. Oncogene 28(31):2773–2783. https://doi.org/10.1038/onc.2009.135

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Mazumdar A, Poage GM, Shepherd J, Tsimelzon A, Hartman ZC, Den Hollander P, Hill J, Zhang Y, Chang J, Hilsenbeck SG, Fuqua S, Kent Osborne C, Mills GB, Brown PH (2016) Analysis of phosphatases in ER-negative breast cancers identifies DUSP4 as a critical regulator of growth and invasion. Breast Cancer Res Treat 158(3):441–454. https://doi.org/10.1007/s10549-016-3892-y

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Sieben NL, Oosting J, Flanagan AM, Prat J, Roemen GM, Kolkman-Uljee SM, van Eijk R, Cornelisse CJ, Fleuren GJ, van Engeland M (2005) Differential gene expression in ovarian tumors reveals Dusp 4 and Serpina 5 as key regulators for benign behavior of serous borderline tumors. J Clin Oncol 23(29):7257–7264. https://doi.org/10.1200/JCO.2005.02.2541

    Article  PubMed  CAS  Google Scholar 

  81. Lin SC, Chien CW, Lee JC, Yeh YC, Hsu KF, Lai YY, Lin SC, Tsai SJ (2011) Suppression of dual-specificity phosphatase-2 by hypoxia increases chemoresistance and malignancy in human cancer cells. J Clin Invest 121(5):1905–1916. https://doi.org/10.1172/JCI44362

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Perander M, Al-Mahdi R, Jensen TC, Nunn JA, Kildalsen H, Johansen B, Gabrielsen M, Keyse SM, Seternes OM (2017) Regulation of atypical MAP kinases ERK3 and ERK4 by the phosphatase DUSP2. Sci Rep 7:43471. https://doi.org/10.1038/srep43471

    Article  PubMed  PubMed Central  Google Scholar 

  83. Yin Y, Liu YX, Jin YJ, Hall EJ, Barrett JC (2003) PAC1 phosphatase is a transcription target of p53 in signalling apoptosis and growth suppression. Nature 422(6931):527–531. https://doi.org/10.1038/nature01519

    Article  PubMed  CAS  Google Scholar 

  84. Lammers T, Lavi S (2007) Role of type 2C protein phosphatases in growth regulation and in cellular stress signaling. Crit Rev Biochem Mol Biol 42(6):437–461. https://doi.org/10.1080/10409230701693342

    Article  PubMed  CAS  Google Scholar 

  85. Lu G, Wang Y (2008) Functional diversity of mammalian type 2C protein phosphatase isoforms: new tales from an old family. Clin Exp Pharmacol Physiol 35(2):107–112. https://doi.org/10.1111/j.1440-1681.2007.04843.x

    Article  PubMed  CAS  Google Scholar 

  86. Shi Y (2009) Serine/threonine phosphatases: mechanism through structure. Cell 139(3):468–484. https://doi.org/10.1016/j.cell.2009.10.006

    Article  PubMed  CAS  Google Scholar 

  87. Hanada M, Kobayashi T, Ohnishi M, Ikeda S, Wang H, Katsura K, Yanagawa Y, Hiraga A, Kanamaru R, Tamura S (1998) Selective suppression of stress-activated protein kinase pathway by protein phosphatase 2C in mammalian cells. FEBS Lett 437(3):172–176

    Article  PubMed  CAS  Google Scholar 

  88. Li R, Gong Z, Pan C, Xie DD, Tang JY, Cui M, Xu YF, Yao W, Pang Q, Xu ZG, Li MY, Yu X, Sun JP (2013) Metal-dependent protein phosphatase 1A functions as an extracellular signal-regulated kinase phosphatase. FEBS J 280(11):2700–2711. https://doi.org/10.1111/febs.12275

    Article  PubMed  CAS  Google Scholar 

  89. Lammers T, Peschke P, Ehemann V, Debus J, Slobodin B, Lavi S, Huber P (2007) Role of PP2Calpha in cell growth, in radio- and chemosensitivity, and in tumorigenicity. Mol Cancer 6:65. https://doi.org/10.1186/1476-4598-6-65

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Ofek P, Ben-Meir D, Kariv-Inbal Z, Oren M, Lavi S (2003) Cell cycle regulation and p53 activation by protein phosphatase 2C alpha. J Biol Chem 278(16):14299–14305. https://doi.org/10.1074/jbc.M211699200

    Article  PubMed  CAS  Google Scholar 

  91. Yang J, Yuan D, Li J, Zheng S, Wang B (2016) miR-186 downregulates protein phosphatase PPM1B in bladder cancer and mediates G1-S phase transition. Tumour Biol 37(4):4331–4341. https://doi.org/10.1007/s13277-015-4117-4

    Article  PubMed  CAS  Google Scholar 

  92. Zhou Y, Zhao Y, Gao Y, Hu W, Qu Y, Lou N, Zhu Y, Zhang X, Yang H (2017) Hepatitis C virus NS3 protein enhances hepatocellular carcinoma cell invasion by promoting PPM1A ubiquitination and degradation. J Exp Clin Cancer Res 36(1):42. https://doi.org/10.1186/s13046-017-0510-8

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Dang CV (2012) MYC on the path to cancer. Cell 149(1):22–35. https://doi.org/10.1016/j.cell.2012.03.003

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Dani C, Blanchard JM, Piechaczyk M, El Sabouty S, Marty L, Jeanteur P (1984) Extreme instability of myc mRNA in normal and transformed human cells. Proc Natl Acad Sci USA 81(22):7046–7050

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Hann SR, Eisenman RN (1984) Proteins encoded by the human c-myc oncogene: differential expression in neoplastic cells. Mol Cell Biol 4(11):2486–2497

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Farrell AS, Sears RC (2014) MYC degradation. Cold Spring Harb Perspect Med. https://doi.org/10.1101/cshperspect.a014365

    Article  PubMed  PubMed Central  Google Scholar 

  97. Farrell AS, Pelz C, Wang X, Daniel CJ, Wang Z, Su Y, Janghorban M, Zhang X, Morgan C, Impey S, Sears RC (2013) Pin1 regulates the dynamics of c-Myc DNA binding to facilitate target gene regulation and oncogenesis. Mol Cell Biol 33(15):2930–2949. https://doi.org/10.1128/MCB.01455-12

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Sanchez-Arevalo Lobo VJ, Doni M, Verrecchia A, Sanulli S, Faga G, Piontini A, Bianchi M, Conacci-Sorrell M, Mazzarol G, Peg V, Losa JH, Ronchi P, Ponzoni M, Eisenman RN, Doglioni C, Amati B (2013) Dual regulation of Myc by Abl. Oncogene 32(45):5261–5271. https://doi.org/10.1038/onc.2012.621

    Article  PubMed  CAS  Google Scholar 

  99. Arnold HK, Sears RC (2006) Protein phosphatase 2A regulatory subunit B56alpha associates with c-myc and negatively regulates c-myc accumulation. Mol Cell Biol 26(7):2832–2844. https://doi.org/10.1128/MCB.26.7.2832-2844.2006

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Liu L, Eisenman RN (2012) Regulation of c-myc protein abundance by a protein phosphatase 2A-glycogen synthase kinase 3beta-negative feedback pathway. Genes Cancer 3(1):23–36. https://doi.org/10.1177/1947601912448067

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Lambrecht C, Libbrecht L, Sagaert X, Pauwels P, Hoorne Y, Crowther J, Louis JV, Sents W, Sablina A, Janssens V (2017) Loss of protein phosphatase 2A regulatory subunit B56delta promotes spontaneous tumorigenesis in vivo. Oncogene. https://doi.org/10.1038/onc.2017.350

    Article  PubMed  Google Scholar 

  102. Xu J, Wong EY, Cheng C, Li J, Sharkar MT, Xu CY, Chen B, Sun J, Jing D, Xu PX (2014) Eya1 interacts with Six2 and Myc to regulate expansion of the nephron progenitor pool during nephrogenesis. Dev Cell 31(4):434–447. https://doi.org/10.1016/j.devcel.2014.10.015

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Li J, Rodriguez Y, Cheng C, Zeng L, Wong EY, Xu CY, Zhou MM, Xu PX (2017) EYA1’s conformation specificity in dephosphorylating phosphothreonine in Myc and Its activity on myc stabilization in breast cancer. Mol Cell Biol. https://doi.org/10.1128/MCB.00499-16

    Article  PubMed  PubMed Central  Google Scholar 

  104. Yeh E, Cunningham M, Arnold H, Chasse D, Monteith T, Ivaldi G, Hahn WC, Stukenberg PT, Shenolikar S, Uchida T, Counter CM, Nevins JR, Means AR, Sears R (2004) A signalling pathway controlling c-Myc degradation that impacts oncogenic transformation of human cells. Nat Cell Biol 6(4):308–318. https://doi.org/10.1038/ncb1110

    Article  PubMed  CAS  Google Scholar 

  105. Zhou H, Zhang L, Vartuli RL, Ford HL, Zhao R (2017) The Eya phosphatase: its unique role in cancer. Int J Biochem Cell Biol. https://doi.org/10.1016/j.biocel.2017.09.001

    Article  PubMed  Google Scholar 

  106. Tan J, Lee PL, Li Z, Jiang X, Lim YC, Hooi SC, Yu Q (2010) B55beta-associated PP2A complex controls PDK1-directed myc signaling and modulates rapamycin sensitivity in colorectal cancer. Cancer Cell 18(5):459–471. https://doi.org/10.1016/j.ccr.2010.10.021

    Article  PubMed  CAS  Google Scholar 

  107. Zhang X, Farrell AS, Daniel CJ, Arnold H, Scanlan C, Laraway BJ, Janghorban M, Lum L, Chen D, Troxell M, Sears R (2012) Mechanistic insight into Myc stabilization in breast cancer involving aberrant Axin1 expression. Proc Natl Acad Sci USA 109(8):2790–2795. https://doi.org/10.1073/pnas.1100764108

    Article  PubMed  Google Scholar 

  108. Young RM, Polsky A, Refaeli Y (2009) TC-PTP is required for the maintenance of MYC-driven B-cell lymphomas. Blood 114(24):5016–5023. https://doi.org/10.1182/blood-2008-12-196709

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. Kleppe M, Lahortiga I, El Chaar T, De Keersmaecker K, Mentens N, Graux C, Van Roosbroeck K, Ferrando AA, Langerak AW, Meijerink JP, Sigaux F, Haferlach T, Wlodarska I, Vandenberghe P, Soulier J, Cools J (2010) Deletion of the protein tyrosine phosphatase gene PTPN2 in T-cell acute lymphoblastic leukemia. Nat Genet 42(6):530–535. https://doi.org/10.1038/ng.587

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. Kleppe M, Soulier J, Asnafi V, Mentens N, Hornakova T, Knoops L, Constantinescu S, Sigaux F, Meijerink JP, Vandenberghe P, Tartaglia M, Foa R, Macintyre E, Haferlach T, Cools J (2011) PTPN2 negatively regulates oncogenic JAK1 in T-cell acute lymphoblastic leukemia. Blood 117(26):7090–7098. https://doi.org/10.1182/blood-2010-10-314286

    Article  PubMed  CAS  Google Scholar 

  111. Kleppe M, Tousseyn T, Geissinger E, Kalender Atak Z, Aerts S, Rosenwald A, Wlodarska I, Cools J (2011) Mutation analysis of the tyrosine phosphatase PTPN2 in Hodgkin’s lymphoma and T-cell non-Hodgkin’s lymphoma. Haematologica 96(11):1723–1727. https://doi.org/10.3324/haematol.2011.041921

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  112. Shields BJ, Wiede F, Gurzov EN, Wee K, Hauser C, Zhu HJ, Molloy TJ, O’Toole SA, Daly RJ, Sutherland RL, Mitchell CA, McLean CA, Tiganis T (2013) TCPTP regulates SFK and STAT3 signaling and is lost in triple-negative breast cancers. Mol Cell Biol 33(3):557–570. https://doi.org/10.1128/MCB.01016-12

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  113. Bowman T, Broome MA, Sinibaldi D, Wharton W, Pledger WJ, Sedivy JM, Irby R, Yeatman T, Courtneidge SA, Jove R (2001) Stat3-mediated Myc expression is required for Src transformation and PDGF-induced mitogenesis. Proc Natl Acad Sci USA 98(13):7319–7324. https://doi.org/10.1073/pnas.131568898

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  114. Bhat M, Robichaud N, Hulea L, Sonenberg N, Pelletier J, Topisirovic I (2015) Targeting the translation machinery in cancer. Nat Rev Drug Discov 14(4):261–278. https://doi.org/10.1038/nrd4505

    Article  PubMed  CAS  Google Scholar 

  115. Li Y, Yue P, Deng X, Ueda T, Fukunaga R, Khuri FR, Sun SY (2010) Protein phosphatase 2A negatively regulates eukaryotic initiation factor 4E phosphorylation and eIF4F assembly through direct dephosphorylation of Mnk and eIF4E. Neoplasia 12(10):848–855

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  116. Guan L, Song K, Pysz MA, Curry KJ, Hizli AA, Danielpour D, Black AR, Black JD (2007) Protein kinase C-mediated down-regulation of cyclin D1 involves activation of the translational repressor 4E-BP1 via a phosphoinositide 3-kinase/Akt-independent, protein phosphatase 2A-dependent mechanism in intestinal epithelial cells. J Biol Chem 282(19):14213–14225. https://doi.org/10.1074/jbc.M610513200

    Article  PubMed  CAS  Google Scholar 

  117. Liu J, Stevens PD, Eshleman NE, Gao T (2013) Protein phosphatase PPM1G regulates protein translation and cell growth by dephosphorylating 4E binding protein 1 (4E-BP1). J Biol Chem 288(32):23225–23233. https://doi.org/10.1074/jbc.M113.492371

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  118. Khoronenkova SV, Dianova II, Ternette N, Kessler BM, Parsons JL, Dianov GL (2012) ATM-dependent downregulation of USP7/HAUSP by PPM1G activates p53 response to DNA damage. Mol Cell 45(6):801–813. https://doi.org/10.1016/j.molcel.2012.01.021

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  119. Xu K, Wang L, Feng W, Feng Y, Shu HK (2016) Phosphatidylinositol-3 kinase-dependent translational regulation of Id1 involves the PPM1G phosphatase. Oncogene 35(44):5807–5816. https://doi.org/10.1038/onc.2016.115

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Liu J, Stevens PD, Gao T (2011) mTOR-dependent regulation of PHLPP expression controls the rapamycin sensitivity in cancer cells. J Biol Chem 286(8):6510–6520. https://doi.org/10.1074/jbc.M110.183087

    Article  PubMed  CAS  Google Scholar 

  121. Cragg MS, Harris C, StRASser A, Scott CL (2009) Unleashing the power of inhibitors of oncogenic kinases through BH3 mimetics. Nat Rev Cancer 9(5):321–326. https://doi.org/10.1038/nrc2615

    Article  PubMed  CAS  Google Scholar 

  122. Kelly GL, StRASser A (2011) The essential role of evasion from cell death in cancer. Adv Cancer Res 111:39–96. https://doi.org/10.1016/B978-0-12-385524-4.00002-7

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  123. Brentnall M, Rodriguez-Menocal L, De Guevara RL, Cepero E, Boise LH (2013) Caspase-9, caspase-3 and caspase-7 have distinct roles during intrinsic apoptosis. BMC Cell Biol 14:32. https://doi.org/10.1186/1471-2121-14-32

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  124. Shamas-Din A, Brahmbhatt H, Leber B, Andrews DW (2011) BH3-only proteins: orchestrators of apoptosis. Biochim Biophys Acta 1813(4):508–520. https://doi.org/10.1016/j.bbamcr.2010.11.024

    Article  PubMed  CAS  Google Scholar 

  125. Czabotar PE, Lessene G, StRASser A, Adams JM (2014) Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol 15(1):49–63. https://doi.org/10.1038/nrm3722

    Article  PubMed  CAS  Google Scholar 

  126. Kim J, Parrish AB, Kurokawa M, Matsuura K, Freel CD, Andersen JL, Johnson CE, Kornbluth S (2012) Rsk-mediated phosphorylation and 14-3-3varepsilon binding of Apaf-1 suppresses cytochrome c-induced apoptosis. EMBO J 31(5):1279–1292. https://doi.org/10.1038/emboj.2011.491

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  127. Serrano BP, Szydlo HS, Alfandari DR, Hardy JA (2017) Active-site adjacent phosphorylation at Tyr-397 by c-Abl kinase inactivates caspase-9. J Biol Chem. https://doi.org/10.1074/jbc.M117.811976

    Article  PubMed Central  PubMed  Google Scholar 

  128. Raina D, Pandey P, Ahmad R, Bharti A, Ren J, Kharbanda S, Weichselbaum R, Kufe D (2005) c-Abl tyrosine kinase regulates caspase-9 autocleavage in the apoptotic response to DNA damage. J Biol Chem 280(12):11147–11151. https://doi.org/10.1074/jbc.M413787200

    Article  PubMed  CAS  Google Scholar 

  129. Allan LA, Morrice N, Brady S, Magee G, Pathak S, Clarke PR (2003) Inhibition of caspase-9 through phosphorylation at Thr 125 by ERK MAPK. Nat Cell Biol 5(7):647–654. https://doi.org/10.1038/ncb1005

    Article  PubMed  CAS  Google Scholar 

  130. Dessauge F, Cayla X, Albar JP, Fleischer A, Ghadiri A, Duhamel M, Rebollo A (2006) Identification of PP1alpha as a caspase-9 regulator in IL-2 deprivation-induced apoptosis. J Immunol 177(4):2441–2451

    Article  PubMed  CAS  Google Scholar 

  131. Lowman XH, McDonnell MA, Kosloske A, Odumade OA, Jenness C, Karim CB, Jemmerson R, Kelekar A (2010) The proapoptotic function of Noxa in human leukemia cells is regulated by the kinase Cdk5 and by glucose. Mol Cell 40(5):823–833. https://doi.org/10.1016/j.molcel.2010.11.035

    Article  PubMed  CAS  Google Scholar 

  132. Karim CB, Espinoza-Fonseca LM, James ZM, Hanse EA, Gaynes JS, Thomas DD, Kelekar A (2015) Structural mechanism for regulation of Bcl-2 protein noxa by phosphorylation. Sci Rep 5:14557. https://doi.org/10.1038/srep14557

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  133. Shao Y, Aplin AE (2012) ERK2 phosphorylation of serine 77 regulates Bmf pro-apoptotic activity. Cell Death Dis 3:e253. https://doi.org/10.1038/cddis.2011.137

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  134. Fricker M, O’Prey J, Tolkovsky AM, Ryan KM (2010) Phosphorylation of Puma modulates its apoptotic function by regulating protein stability. Cell Death Dis 1:e59. https://doi.org/10.1038/cddis.2010.38

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  135. Ley R, Balmanno K, Hadfield K, Weston C, Cook SJ (2003) Activation of the ERK1/2 signaling pathway promotes phosphorylation and proteasome-dependent degradation of the BH3-only protein. Bim J Biol Chem 278(21):18811–18816. https://doi.org/10.1074/jbc.M301010200

    Article  PubMed  CAS  Google Scholar 

  136. Li YM, Wen Y, Zhou BP, Kuo HP, Ding Q, Hung MC (2003) Enhancement of Bik antitumor effect by Bik mutants. Cancer Res 63(22):7630–7633

    PubMed  CAS  Google Scholar 

  137. Verma S, Zhao LJ, Chinnadurai G (2001) Phosphorylation of the pro-apoptotic protein BIK: mapping of phosphorylation sites and effect on apoptosis. J Biol Chem 276(7):4671–4676. https://doi.org/10.1074/jbc.M008983200

    Article  PubMed  CAS  Google Scholar 

  138. Kutuk O, Letai A (2008) Regulation of Bcl-2 family proteins by posttranslational modifications. Curr Mol Med 8(2):102–118

    Article  PubMed  CAS  Google Scholar 

  139. Chiang CW, Harris G, Ellig C, Masters SC, Subramanian R, Shenolikar S, Wadzinski BE, Yang E (2001) Protein phosphatase 2A activates the proapoptotic function of BAD in interleukin- 3-dependent lymphoid cells by a mechanism requiring 14-3-3 dissociation. Blood 97(5):1289–1297

    Article  PubMed  CAS  Google Scholar 

  140. Klumpp S, Selke D, Krieglstein J (2003) Protein phosphatase type 2C dephosphorylates BAD. Neurochem Int 42(7):555–560

    Article  PubMed  CAS  Google Scholar 

  141. Ayllon V, Martinez AC, Garcia A, Cayla X, Rebollo A (2000) Protein phosphatase 1alpha is a RAS-activated Bad phosphatase that regulates interleukin-2 deprivation-induced apoptosis. EMBO J 19(10):2237–2246. https://doi.org/10.1093/emboj/19.10.2237

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  142. Wang HG, Pathan N, Ethell IM, Krajewski S, Yamaguchi Y, Shibasaki F, McKeon F, Bobo T, Franke TF, Reed JC (1999) Ca2+ -induced apoptosis through calcineurin dephosphorylation of BAD. Science 284(5412):339–343

    Article  PubMed  CAS  Google Scholar 

  143. Polzien L, Baljuls A, Rennefahrt UE, Fischer A, Schmitz W, Zahedi RP, Sickmann A, Metz R, Albert S, Benz R, Hekman M, Rapp UR (2009) Identification of novel in vivo phosphorylation sites of the human proapoptotic protein BAD: pore-forming activity of BAD is regulated by phosphorylation. J Biol Chem 284(41):28004–28020. https://doi.org/10.1074/jbc.M109.010702

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  144. Correia C, Lee SH, Meng XW, Vincelette ND, Knorr KL, Ding H, Nowakowski GS, Dai H, Kaufmann SH (2015) Emerging understanding of Bcl-2 biology: implications for neoplastic progression and treatment. Biochim Biophys Acta 1853(7):1658–1671. https://doi.org/10.1016/j.bbamcr.2015.03.012

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  145. Ruvolo PP, Clark W, Mumby M, Gao F, May WS (2002) A functional role for the B56 alpha-subunit of protein phosphatase 2A in ceramide-mediated regulation of Bcl2 phosphorylation status and function. J Biol Chem 277(25):22847–22852. https://doi.org/10.1074/jbc.M201830200

    Article  PubMed  CAS  Google Scholar 

  146. Low IC, Loh T, Huang Y, Virshup DM, Pervaiz S (2014) Ser70 phosphorylation of Bcl-2 by selective tyrosine nitration of PP2A-B56delta stabilizes its antiapoptotic activity. Blood 124(14):2223–2234. https://doi.org/10.1182/blood-2014-03-563296

    Article  PubMed  CAS  Google Scholar 

  147. Ishikawa Y, Kusaka E, Enokido Y, Ikeuchi T, Hatanaka H (2003) Regulation of Bax translocation through phosphorylation at Ser-70 of Bcl-2 by MAP kinase in NO-induced neuronal apoptosis. Mol Cell Neurosci 24(2):451–459

    Article  PubMed  CAS  Google Scholar 

  148. Wei Y, Pattingre S, Sinha S, Bassik M, Levine B (2008) JNK1-mediated phosphorylation of Bcl-2 regulates starvation-induced autophagy. Mol Cell 30(6):678–688. https://doi.org/10.1016/j.molcel.2008.06.001

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  149. Haldar S, Chintapalli J, Croce CM (1996) Taxol induces bcl-2 phosphorylation and death of prostate cancer cells. Cancer Res 56(6):1253–1255

    PubMed  CAS  Google Scholar 

  150. Poruchynsky MS, Wang EE, Rudin CM, Blagosklonny MV, Fojo T (1998) Bcl-xL is phosphorylated in malignant cells following microtubule disruption. Cancer Res 58(15):3331–3338

    PubMed  CAS  Google Scholar 

  151. Upreti M, Galitovskaya EN, Chu R, Tackett AJ, Terrano DT, Granell S, Chambers TC (2008) Identification of the major phosphorylation site in Bcl-xL induced by microtubule inhibitors and analysis of its functional significance. J Biol Chem 283(51):35517–35525. https://doi.org/10.1074/jbc.M805019200

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  152. Sakurikar N, Eichhorn JM, Chambers TC (2012) Cyclin-dependent kinase-1 (Cdk1)/cyclin B1 dictates cell fate after mitotic arrest via phosphoregulation of antiapoptotic Bcl-2 proteins. J Biol Chem 287(46):39193–39204. https://doi.org/10.1074/jbc.M112.391854

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  153. Eichhorn JM, Sakurikar N, Alford SE, Chu R, Chambers TC (2013) Critical role of anti-apoptotic Bcl-2 protein phosphorylation in mitotic death. Cell Death Dis 4:e834. https://doi.org/10.1038/cddis.2013.360

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  154. Haschka MD, Soratroi C, Kirschnek S, Hacker G, Hilbe R, Geley S, Villunger A, Fava LL (2015) The NOXA-MCL1-BIM axis defines lifespan on extended mitotic arrest. Nat Commun 6:6891. https://doi.org/10.1038/ncomms7891

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  155. Schmitt E, Beauchemin M, Bertrand R (2007) Nuclear colocalization and interaction between bcl-xL and cdk1(cdc2) during G2/M cell-cycle checkpoint. Oncogene 26(40):5851–5865. https://doi.org/10.1038/sj.onc.1210396

    Article  PubMed  CAS  Google Scholar 

  156. Dai H, Ding H, Meng XW, Lee SH, Schneider PA, Kaufmann SH (2013) Contribution of Bcl-2 phosphorylation to Bak binding and drug resistance. Cancer Res 73(23):6998–7008. https://doi.org/10.1158/0008-5472.CAN-13-0940

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  157. Yamamoto K, Ichijo H, Korsmeyer SJ (1999) BCL-2 is phosphorylated and inactivated by an ASK1/Jun N-terminal protein kinase pathway normally activated at G(2)/M. Mol Cell Biol 19(12):8469–8478

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  158. Antony R, Lukiw WJ, Bazan NG (2010) Neuroprotectin D1 induces dephosphorylation of Bcl-xL in a PP2A-dependent manner during oxidative stress and promotes retinal pigment epithelial cell survival. J Biol Chem 285(24):18301–18308. https://doi.org/10.1074/jbc.M109.095232

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  159. Basu A, Haldar S (2003) Identification of a novel Bcl-xL phosphorylation site regulating the sensitivity of taxol- or 2-methoxyestradiol-induced apoptosis. FEBS Lett 538(1–3):41–47

    Article  PubMed  CAS  Google Scholar 

  160. Nifoussi SK, Ratcliffe NR, Ornstein DL, Kasof G, Strack S, Craig RW (2014) Inhibition of protein phosphatase 2A (PP2A) prevents Mcl-1 protein dephosphorylation at the Thr-163/Ser-159 phosphodegron, dramatically reducing expression in Mcl-1-amplified lymphoma cells. J Biol Chem 289(32):21950–21959. https://doi.org/10.1074/jbc.M114.587873

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  161. Kajihara R, Sakamoto H, Tanabe K, Takemoto K, Tasaki M, Ando Y, Inui S (2014) Protein phosphatase 6 controls BCR-induced apoptosis of WEHI-231 cells by regulating ubiquitination of Bcl-xL. J Immunol 192(12):5720–5729. https://doi.org/10.4049/jimmunol.1302643

    Article  PubMed  CAS  Google Scholar 

  162. Ayllon V, Cayla X, Garcia A, Fleischer A, Rebollo A (2002) The anti-apoptotic molecules Bcl-xL and Bcl-w target protein phosphatase 1alpha to Bad. Eur J Immunol 32(7):1847–1855. https://doi.org/10.1002/1521-4141(200207)32:7<1847::AID-IMMU1847>3.0.CO;2-7

    Article  PubMed  CAS  Google Scholar 

  163. Xin M, Deng X (2006) Protein phosphatase 2A enhances the proapoptotic function of Bax through dephosphorylation. J Biol Chem 281(27):18859–18867. https://doi.org/10.1074/jbc.M512543200

    Article  PubMed  CAS  Google Scholar 

  164. Puthalakath H, O’Reilly LA, Gunn P, Lee L, Kelly PN, Huntington ND, Hughes PD, Michalak EM, McKimm-Breschkin J, Motoyama N, Gotoh T, Akira S, Bouillet P, StRASser A (2007) ER stress triggers apoptosis by activating BH3-only protein Bim. Cell 129(7):1337–1349. https://doi.org/10.1016/j.cell.2007.04.027

    Article  PubMed  CAS  Google Scholar 

  165. Kiyota M, Kuroda J, Yamamoto-Sugitani M, Shimura Y, Nakayama R, Nagoshi H, Mizutani S, Chinen Y, Sasaki N, Sakamoto N, Kobayashi T, Matsumoto Y, Horiike S, Taniwaki M (2013) FTY720 induces apoptosis of chronic myelogenous leukemia cells via dual activation of BIM and BID and overcomes various types of resistance to tyrosine kinase inhibitors. Apoptosis 18(11):1437–1446. https://doi.org/10.1007/s10495-013-0882-y

    Article  PubMed  CAS  Google Scholar 

  166. Lin CF, Chen CL, Chiang CW, Jan MS, Huang WC, Lin YS (2007) GSK-3beta acts downstream of PP2A and the PI 3-kinase-Akt pathway, and upstream of caspase-2 in ceramide-induced mitochondrial apoptosis. J Cell Sci 120(Pt 16):2935–2943. https://doi.org/10.1242/jcs.03473

    Article  PubMed  CAS  Google Scholar 

  167. Thomas LW, Lam C, Edwards SW (2010) Mcl-1; the molecular regulation of protein function. FEBS Lett 584(14):2981–2989. https://doi.org/10.1016/j.febslet.2010.05.061

    Article  PubMed  CAS  Google Scholar 

  168. Kobayashi S, Lee SH, Meng XW, Mott JL, Bronk SF, Werneburg NW, Craig RW, Kaufmann SH, Gores GJ (2007) Serine 64 phosphorylation enhances the antiapoptotic function of Mcl-1. J Biol Chem 282(25):18407–18417. https://doi.org/10.1074/jbc.M610010200

    Article  PubMed  CAS  Google Scholar 

  169. Maurer U, Charvet C, Wagman AS, Dejardin E, Green DR (2006) Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization and apoptosis by destabilization of MCL-1. Mol Cell 21(6):749–760. https://doi.org/10.1016/j.molcel.2006.02.009

    Article  PubMed  CAS  Google Scholar 

  170. Ding Q, He X, Hsu JM, Xia W, Chen CT, Li LY, Lee DF, Liu JC, Zhong Q, Wang X, Hung MC (2007) Degradation of Mcl-1 by beta-TrCP mediates glycogen synthase kinase 3-induced tumor suppression and chemosensitization. Mol Cell Biol 27(11):4006–4017. https://doi.org/10.1128/MCB.00620-06

    Article  PubMed  CAS  Google Scholar 

  171. Mojsa B, Lassot I, Desagher S (2014) Mcl-1 ubiquitination: unique regulation of an essential survival protein. Cells 3(2):418–437. https://doi.org/10.3390/cells3020418

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  172. Liu Q, Zhao X, Frissora F, Ma Y, Santhanam R, Jarjoura D, Lehman A, Perrotti D, Chen CS, Dalton JT, Muthusamy N, Byrd JC (2008) FTY720 demonstrates promising preclinical activity for chronic lymphocytic leukemia and lymphoblastic leukemia/lymphoma. Blood 111(1):275–284. https://doi.org/10.1182/blood-2006-10-053884

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  173. Christensen DJ, Chen Y, Oddo J, Matta KM, Neil J, Davis ED, Volkheimer AD, Lanasa MC, Friedman DR, Goodman BK, Gockerman JP, Diehl LF, de Castro CM, Moore JO, Vitek MP, Weinberg JB (2011) SET oncoprotein overexpression in B-cell chronic lymphocytic leukemia and non-Hodgkin lymphoma: a predictor of aggressive disease and a new treatment target. Blood 118(15):4150–4158. https://doi.org/10.1182/blood-2011-04-351072

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  174. Wang CY, Lin YS, Su WC, Chen CL, Lin CF (2009) Glycogen synthase kinase-3 and Omi/HtrA2 induce annexin A2 cleavage followed by cell cycle inhibition and apoptosis. Mol Biol Cell 20(19):4153–4161. https://doi.org/10.1091/mbc.E09-02-0174

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  175. Nica AF, Tsao CC, Watt JC, Jiffar T, Kurinna S, JuRASz P, Konopleva M, Andreeff M, Radomski MW, Ruvolo PP (2008) Ceramide promotes apoptosis in chronic myelogenous leukemia-derived K562 cells by a mechanism involving caspase-8 and JNK. Cell Cycle 7(21):3362–3370. https://doi.org/10.4161/cc.7.21.6894

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  176. Morad SA, Cabot MC (2013) Ceramide-orchestrated signalling in cancer cells. Nat Rev Cancer 13(1):51–65. https://doi.org/10.1038/nrc3398

    Article  PubMed  CAS  Google Scholar 

  177. Desagher S, Osen-Sand A, Montessuit S, Magnenat E, Vilbois F, Hochmann A, Journot L, Antonsson B, Martinou JC (2001) Phosphorylation of bid by casein kinases I and II regulates its cleavage by caspase 8. Mol Cell 8(3):601–611

    Article  PubMed  CAS  Google Scholar 

  178. Hellwig CT, Ludwig-Galezowska AH, Concannon CG, Litchfield DW, Prehn JH, Rehm M (2010) Activity of protein kinase CK2 uncouples Bid cleavage from caspase-8 activation. J Cell Sci 123(Pt 9):1401–1406. https://doi.org/10.1242/jcs.061143

    Article  PubMed  CAS  Google Scholar 

  179. Yuan XJ, Whang YE (2002) PTEN sensitizes prostate cancer cells to death receptor-mediated and drug-induced apoptosis through a FADD-dependent pathway. Oncogene 21(2):319–327. https://doi.org/10.1038/sj.onc.1205054

    Article  PubMed  CAS  Google Scholar 

  180. Chakrabandhu K, Huault S, Durivault J, Lang K, Ta Ngoc L, Bole A, Doma E, Derijard B, Gerard JP, Pierres M, Hueber AO (2016) An evolution-guided analysis reveals a multi-signaling regulation of fas by tyrosine phosphorylation and its implication in human cancers. PLoS Biol 14(3):e1002401. https://doi.org/10.1371/journal.pbio.1002401

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  181. Jia SH, Parodo J, Kapus A, Rotstein OD, Marshall JC (2008) Dynamic regulation of neutrophil survival through tyrosine phosphorylation or dephosphorylation of caspase-8. J Biol Chem 283(9):5402–5413. https://doi.org/10.1074/jbc.M706462200

    Article  PubMed  CAS  Google Scholar 

  182. Gloire G, Charlier E, Piette J (2008) Regulation of CD95/APO-1/Fas-induced apoptosis by protein phosphatases. Biochem Pharmacol 76(11):1451–1458. https://doi.org/10.1016/j.bcp.2008.06.023

    Article  PubMed  CAS  Google Scholar 

  183. Foehr ED, Lorente G, Vincent V, Nikolich K, Urfer R (2005) FAS associated phosphatase (FAP-1) blocks apoptosis of astrocytomas through dephosphorylation of FAS. J Neurooncol 74(3):241–248. https://doi.org/10.1007/s11060-004-7202-x

    Article  PubMed  CAS  Google Scholar 

  184. Ivanov VN, Lopez Bergami P, Maulit G, Sato TA, Sassoon D, Ronai Z (2003) FAP-1 association with Fas (Apo-1) inhibits Fas expression on the cell surface. Mol Cell Biol 23(10):3623–3635

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  185. He RJ, Yu ZH, Zhang RY, Zhang ZY (2014) Protein tyrosine phosphatases as potential therapeutic targets. Acta Pharmacol Sin 35(10):1227–1246. https://doi.org/10.1038/aps.2014.80

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  186. Ivanov VN, Ronai Z, Hei TK (2006) Opposite roles of FAP-1 and dynamin in the regulation of Fas (CD95) translocation to the cell surface and susceptibility to Fas ligand-mediated apoptosis. J Biol Chem 281(3):1840–1852. https://doi.org/10.1074/jbc.M509866200

    Article  PubMed  CAS  Google Scholar 

  187. Wieckowski E, AtaRAShi Y, Stanson J, Sato TA, Whiteside TL (2007) FAP-1-mediated activation of NF-kappaB induces resistance of head and neck cancer to Fas-induced apoptosis. J Cell Biochem 100(1):16–28. https://doi.org/10.1002/jcb.20922

    Article  PubMed  CAS  Google Scholar 

  188. Srikanth S, Franklin CC, Duke RC, Kraft RS (1999) Human DU145 prostate cancer cells overexpressing mitogen-activated protein kinase phosphatase-1 are resistant to Fas ligand-induced mitochondrial perturbations and cellular apoptosis. Mol Cell Biochem 199(1–2):169–178

    Article  PubMed  CAS  Google Scholar 

  189. Harmala-BRASken AS, Mikhailov A, Soderstrom TS, Meinander A, Holmstrom TH, Damuni Z, Eriksson JE (2003) Type-2A protein phosphatase activity is required to maintain death receptor responsiveness. Oncogene 22(48):7677–7686. https://doi.org/10.1038/sj.onc.1207077

    Article  PubMed  CAS  Google Scholar 

  190. Alvarado-Kristensson M, Andersson T (2005) Protein phosphatase 2A regulates apoptosis in neutrophils by dephosphorylating both p38 MAPK and its substrate caspase 3. J Biol Chem 280(7):6238–6244. https://doi.org/10.1074/jbc.M409718200

    Article  PubMed  CAS  Google Scholar 

  191. Chatfield K, Eastman A (2004) Inhibitors of protein phosphatases 1 and 2A differentially prevent intrinsic and extrinsic apoptosis pathways. Biochem Biophys Res Commun 323(4):1313–1320. https://doi.org/10.1016/j.bbrc.2004.09.003

    Article  PubMed  CAS  Google Scholar 

  192. Dillon LM, Miller TW (2014) Therapeutic targeting of cancers with loss of PTEN function. Curr Drug Targets 15(1):65–79

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  193. Sangodkar J, Perl A, Tohme R, Kiselar J, Kastrinsky DB, Zaware N, Izadmehr S, Mazhar S, Wiredja DD, O’Connor CM, Hoon D, Dhawan NS, Schlatzer D, Yao S, Leonard D, Borczuk AC, Gokulrangan G, Wang L, Svenson E, Farrington CC, Yuan E, Avelar RA, Stachnik A, Smith B, Gidwani V, Giannini HM, McQuaid D, McClinch K, Wang Z, Levine AC, Sears RC, Chen EY, Duan Q, Datt M, Haider S, Ma’ayan A, DiFeo A, Sharma N, Galsky MD, Brautigan DL, Ioannou YA, Xu W, Chance MR, Ohlmeyer M, Narla G (2017) Activation of tumor suppressor protein PP2A inhibits KRAS-driven tumor growth. J Clin Invest 127(6):2081–2090. https://doi.org/10.1172/JCI89548

    Article  PubMed  PubMed Central  Google Scholar 

  194. Neviani P, Santhanam R, Oaks JJ, Eiring AM, Notari M, Blaser BW, Liu S, Trotta R, Muthusamy N, Gambacorti-Passerini C, Druker BJ, Cortes J, Marcucci G, Chen CS, Verrills NM, Roy DC, Caligiuri MA, Bloomfield CD, Byrd JC, Perrotti D (2007) FTY720, a new alternative for treating blast crisis chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphocytic leukemia. J Clin Invest 117(9):2408–2421. https://doi.org/10.1172/JCI31095

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  195. Agarwal A, MacKenzie RJ, Pippa R, Eide CA, Oddo J, Tyner JW, Sears R, Vitek MP, Odero MD, Christensen DJ, Druker BJ (2014) Antagonism of SET using OP449 enhances the efficacy of tyrosine kinase inhibitors and overcomes drug resistance in myeloid leukemia. Clin Cancer Res 20(8):2092–2103. https://doi.org/10.1158/1078-0432.CCR-13-2575

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  196. Bollu LR, Mazumdar A, Savage MI, Brown PH (2017) Molecular pathways: targeting protein tyrosine phosphatases in cancer. Clin Cancer Res 23(9):2136–2142. https://doi.org/10.1158/1078-0432.CCR-16-0934

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  197. Hong CS, Ho W, Zhang C, Yang C, Elder JB, Zhuang Z (2015) LB100, a small molecule inhibitor of PP2A with potent chemo- and radio-sensitizing potential. Cancer Biol Ther 16(6):821–833. https://doi.org/10.1080/15384047.2015.1040961

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  198. O’Connor CM, Perl A, Leonard D, Sangodkar J, Narla G (2017) Therapeutic targeting of PP2A. Int J Biochem Cell Biol. https://doi.org/10.1016/j.biocel.2017.10.008

    Article  PubMed  Google Scholar 

  199. Ramaswamy K, Spitzer B, Kentsis A (2015) Therapeutic re-activation of protein phosphatase 2A in acute myeloid leukemia. Front Oncol 5:16. https://doi.org/10.3389/fonc.2015.00016

    Article  PubMed  PubMed Central  Google Scholar 

  200. Carratu MR, Signorile A, De Rasmo D, Reale A, Vacca A (2016) Pharmacological activation of protein phosphatase 2 A (PP2A): a novel strategy to fight against human malignancies? Curr Med Chem 23(38):4286–4296

    Article  PubMed  CAS  Google Scholar 

  201. Arriazu E, Pippa R, Odero MD (2016) Protein phosphatase 2A as a therapeutic target in acute myeloid leukemia. Front Oncol 6:78. https://doi.org/10.3389/fonc.2016.00078

    Article  PubMed  PubMed Central  Google Scholar 

  202. Zhang C, Peng Y, Wang F, Tan X, Liu N, Fan S, Wang D, Zhang L, Liu D, Wang T, Wang S, Zhou Y, Su Y, Cheng T, Zhuang Z, Shi C (2010) A synthetic cantharidin analog for the enhancement of doxorubicin suppression of stem cell-derived aggressive sarcoma. Biomaterials 31(36):9535–9543. https://doi.org/10.1016/j.biomaterials.2010.08.059

    Article  PubMed  CAS  Google Scholar 

  203. Nguyen LK, Matallanas D, Croucher DR, von Kriegsheim A, Kholodenko BN (2013) Signalling by protein phosphatases and drug development: a systems-centred view. FEBS J 280(2):751–765. https://doi.org/10.1111/j.1742-4658.2012.08522.x

    Article  PubMed  CAS  Google Scholar 

  204. Behjati S, Tarpey PS, Sheldon H, Martincorena I, Van Loo P, Gundem G, Wedge DC, Ramakrishna M, Cooke SL, Pillay N, Vollan HKM, Papaemmanuil E, Koss H, Bunney TD, Hardy C, Joseph OR, Martin S, Mudie L, Butler A, Teague JW, Patil M, Steers G, Cao Y, Gumbs C, Ingram D, Lazar AJ, Little L, Mahadeshwar H, Protopopov A, Al Sannaa GA, Seth S, Song X, Tang J, Zhang J, Ravi V, Torres KE, Khatri B, Halai D, Roxanis I, Baumhoer D, Tirabosco R, Amary MF, Boshoff C, McDermott U, Katan M, Stratton MR, Futreal PA, Flanagan AM, Harris A, Campbell PJ (2014) Recurrent PTPRB and PLCG1 mutations in angiosarcoma. Nat Genet 46(4):376–379. https://doi.org/10.1038/ng.2921

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  205. Qi Y, Dai Y, Gui S (2016) Protein tyrosine phosphatase PTPRB regulates Src phosphorylation and tumour progression in NSCLC. Clin Exp Pharmacol Physiol 43(10):1004–1012. https://doi.org/10.1111/1440-1681.12610

    Article  PubMed  CAS  Google Scholar 

  206. Munkley J, Lafferty NP, Kalna G, Robson CN, Leung HY, Rajan P, Elliott DJ (2015) Androgen-regulation of the protein tyrosine phosphatase PTPRR activates ERK1/2 signalling in prostate cancer cells. BMC Cancer 15:9. https://doi.org/10.1186/s12885-015-1012-8

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  207. Su PH, Lin YW, Huang RL, Liao YP, Lee HY, Wang HC, Chao TK, Chen CK, Chan MW, Chu TY, Yu MH, Lai HC (2013) Epigenetic silencing of PTPRR activates MAPK signaling, promotes metastasis and serves as a biomarker of invasive cervical cancer. Oncogene 32(1):15–26. https://doi.org/10.1038/onc.2012.29

    Article  PubMed  CAS  Google Scholar 

  208. Suarez Pestana E, Tenev T, Gross S, Stoyanov B, Ogata M, Bohmer FD (1999) The transmembrane protein tyrosine phosphatase RPTPsigma modulates signaling of the epidermal growth factor receptor in A431 cells. Oncogene 18(28):4069–4079. https://doi.org/10.1038/sj.onc.1202794

    Article  PubMed  CAS  Google Scholar 

  209. Morris LG, Taylor BS, Bivona TG, Gong Y, Eng S, Brennan CW, Kaufman A, Kastenhuber ER, Banuchi VE, Singh B, Heguy A, Viale A, Mellinghoff IK, Huse J, Ganly I, Chan TA (2011) Genomic dissection of the epidermal growth factor receptor (EGFR)/PI3K pathway reveals frequent deletion of the EGFR phosphatase PTPRS in head and neck cancers. Proc Natl Acad Sci USA 108(47):19024–19029. https://doi.org/10.1073/pnas.1111963108

    Article  PubMed  PubMed Central  Google Scholar 

  210. Wang Z, Shen D, Parsons DW, Bardelli A, Sager J, Szabo S, Ptak J, Silliman N, Peters BA, van der Heijden MS, Parmigiani G, Yan H, Wang TL, Riggins G, Powell SM, Willson JK, Markowitz S, Kinzler KW, Vogelstein B, Velculescu VE (2004) Mutational analysis of the tyrosine phosphatome in colorectal cancers. Science 304(5674):1164–1166. https://doi.org/10.1126/science.1096096

    Article  PubMed  CAS  Google Scholar 

  211. Elson A, Leder P (1995) Protein-tyrosine phosphatase epsilon. An isoform specifically expressed in mouse mammary tumors initiated by v-Ha-RAS OR neu. J Biol Chem 270(44):26116–26122

    Article  PubMed  CAS  Google Scholar 

  212. Gil-Henn H, Elson A (2003) Tyrosine phosphatase-epsilon activates Src and supports the transformed phenotype of Neu-induced mammary tumor cells. J Biol Chem 278(18):15579–15586. https://doi.org/10.1074/jbc.M210273200

    Article  PubMed  CAS  Google Scholar 

  213. Sadakata H, Okazawa H, Sato T, Supriatna Y, Ohnishi H, Kusakari S, Murata Y, Ito T, Nishiyama U, Minegishi T, Harada A, Matozaki T (2009) SAP-1 is a microvillus-specific protein tyrosine phosphatase that modulates intestinal tumorigenesis. Genes Cells 14(3):295–308. https://doi.org/10.1111/j.1365-2443.2008.01270.x

    Article  PubMed  CAS  Google Scholar 

  214. Seo Y, Matozaki T, Tsuda M, Hayashi Y, Itoh H, Kasuga M (1997) Overexpression of SAP-1, a transmembrane-type protein tyrosine phosphatase, in human colorectal cancers. Biochem Biophys Res Commun 231(3):705–711. https://doi.org/10.1006/bbrc.1997.6139

    Article  PubMed  CAS  Google Scholar 

  215. Xu H, Cai T, Carmona GN, Abuhatzira L, Notkins AL (2016) Small cell lung cancer growth is inhibited by miR-342 through its effect of the target gene IA-2. J Transl Med 14(1):278. https://doi.org/10.1186/s12967-016-1036-0

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  216. Sengelaub CA, Navrazhina K, Ross JB, Halberg N, Tavazoie SF (2016) PTPRN2 and PLCbeta1 promote metastatic breast cancer cell migration through PI(4,5)P2-dependent actin remodeling. EMBO J 35(1):62–76. https://doi.org/10.15252/embj.201591973

    Article  PubMed  CAS  Google Scholar 

  217. Sorokin AV, Nair BC, Wei Y, Aziz KE, Evdokimova V, Hung MC, Chen J (2015) Aberrant Expression of proPTPRN2 in cancer cells confers resistance to apoptosis. Cancer Res 75(9):1846–1858. https://doi.org/10.1158/0008-5472.CAN-14-2718

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  218. Spring K, Fournier P, Lapointe L, Chabot C, Roussy J, Pommey S, Stagg J, Royal I (2015) The protein tyrosine phosphatase DEP-1/PTPRJ promotes breast cancer cell invasion and metastasis. Oncogene 34(44):5536–5547. https://doi.org/10.1038/onc.2015.9

    Article  PubMed  CAS  Google Scholar 

  219. Sun PH, Ye L, Mason MD, Jiang WG (2013) Receptor-like protein tyrosine phosphatase kappa negatively regulates the apoptosis of prostate cancer cells via the JNK pathway. Int J Oncol 43(5):1560–1568. https://doi.org/10.3892/ijo.2013.2082

    Article  PubMed  CAS  Google Scholar 

  220. Novellino L, De Filippo A, Deho P, Perrone F, Pilotti S, Parmiani G, Castelli C (2008) PTPRK negatively regulates transcriptional activity of wild type and mutated oncogenic beta-catenin and affects membrane distribution of beta-catenin/E-cadherin complexes in cancer cells. Cell Signal 20(5):872–883. https://doi.org/10.1016/j.cellsig.2007.12.024

    Article  PubMed  CAS  Google Scholar 

  221. Chen YW, Guo T, Shen L, Wong KY, Tao Q, Choi WW, Au-Yeung RK, Chan YP, Wong ML, Tang JC, Liu WP, Li GD, Shimizu N, Loong F, Tse E, Kwong YL, Srivastava G (2015) Receptor-type tyrosine-protein phosphatase kappa directly targets STAT3 activation for tumor suppression in nasal NK/T-cell lymphoma. Blood 125(10):1589–1600. https://doi.org/10.1182/blood-2014-07-588970

    Article  PubMed  CAS  Google Scholar 

  222. Burgoyne AM, Palomo JM, Phillips-Mason PJ, Burden-Gulley SM, Major DL, Zaremba A, Robinson S, Sloan AE, Vogelbaum MA, Miller RH, Brady-Kalnay SM (2009) PTPmu suppresses glioma cell migration and dispersal. Neuro Oncol 11(6):767–778. https://doi.org/10.1215/15228517-2009-019

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  223. Burgoyne AM, Phillips-Mason PJ, Burden-Gulley SM, Robinson S, Sloan AE, Miller RH, Brady-Kalnay SM (2009) Proteolytic cleavage of protein tyrosine phosphatase mu regulates glioblastoma cell migration. Cancer Res 69(17):6960–6968. https://doi.org/10.1158/0008-5472.CAN-09-0863

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  224. Kaur H, Burden-Gulley SM, Phillips-Mason PJ, Basilion JP, Sloan AE, Brady-Kalnay SM (2012) Protein tyrosine phosphatase mu regulates glioblastoma cell growth and survival in vivo. Neuro Oncol 14(5):561–573. https://doi.org/10.1093/neuonc/nos066

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  225. Sudhir PR, Lin ST, Chia-Wen C, Yang SH, Li AF, Lai RH, Wang MJ, Chen YT, Chen CF, Jou YS, Chen JY (2015) Loss of PTPRM associates with the pathogenic development of colorectal adenoma-carcinoma sequence. Sci Rep 5:9633. https://doi.org/10.1038/srep09633

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  226. Sun PH, Ye L, Mason MD, Jiang WG (2012) Protein tyrosine phosphatase micro (PTP micro or PTPRM), a negative regulator of proliferation and invasion of breast cancer cells, is associated with disease prognosis. PLoS One 7(11):e50183. https://doi.org/10.1371/journal.pone.0050183

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  227. Yuan T, Wang Y, Zhao ZJ, Gu H (2010) Protein-tyrosine phosphatase PTPN9 negatively regulates ErbB2 and epidermal growth factor receptor signaling in breast cancer cells. J Biol Chem 285(20):14861–14870. https://doi.org/10.1074/jbc.M109.099879

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  228. Kodama T, Newberg JY, Kodama M, Rangel R, Yoshihara K, Tien JC, Parsons PH, Wu H, Finegold MJ, Copeland NG, Jenkins NA (2016) Transposon mutagenesis identifies genes and cellular processes driving epithelial-mesenchymal transition in hepatocellular carcinoma. Proc Natl Acad Sci USA 113(24):E3384–E3393. https://doi.org/10.1073/pnas.1606876113

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  229. Li J, Davidson D, Martins Souza C, Zhong MC, Wu N, Park M, Muller WJ, Veillette A (2015) Loss of PTPN12 stimulates progression of ErbB2-dependent breast cancer by enhancing cell survival, migration, and epithelial-to-mesenchymal transition. Mol Cell Biol 35(23):4069–4082. https://doi.org/10.1128/MCB.00741-15

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  230. Wadham C, Gamble JR, Vadas MA, Khew-Goodall Y (2003) The protein tyrosine phosphatase Pez is a major phosphatase of adherens junctions and dephosphorylates beta-catenin. Mol Biol Cell 14(6):2520–2529. https://doi.org/10.1091/mbc.E02-09-0577

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  231. Liu X, Yang N, Figel SA, Wilson KE, Morrison CD, Gelman IH, Zhang J (2013) PTPN14 interacts with and negatively regulates the oncogenic function of YAP. Oncogene 32(10):1266–1273. https://doi.org/10.1038/onc.2012.147

    Article  PubMed  CAS  Google Scholar 

  232. Carlucci A, Porpora M, Garbi C, Galgani M, Santoriello M, Mascolo M, di Lorenzo D, Altieri V, Quarto M, Terracciano L, Gottesman ME, Insabato L, Feliciello A (2010) PTPD1 supports receptor stability and mitogenic signaling in bladder cancer cells. J Biol Chem 285(50):39260–39270. https://doi.org/10.1074/jbc.M110.174706

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  233. Lessard L, Stuible M, Tremblay ML (2010) The two faces of PTP1B in cancer. Biochim Biophys Acta 1804(3):613–619. https://doi.org/10.1016/j.bbapap.2009.09.018

    Article  PubMed  CAS  Google Scholar 

  234. Zanke B, Squire J, Griesser H, Henry M, Suzuki H, Patterson B, Minden M, Mak TW (1994) A hematopoietic protein tyrosine phosphatase (HePTP) gene that is amplified and overexpressed in myeloid malignancies maps to chromosome 1q32.1. Leukemia 8(2):236–244

    PubMed  CAS  Google Scholar 

  235. Gronda M, Arab S, Iafrate B, Suzuki H, Zanke BW (2001) Hematopoietic protein tyrosine phosphatase suppresses extracellular stimulus-regulated kinase activation. Mol Cell Biol 21(20):6851–6858. https://doi.org/10.1128/MCB.21.20.6851-6858.2001

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  236. Glondu-Lassis M, Dromard M, Lacroix-Triki M, Nirde P, Puech C, Knani D, Chalbos D, Freiss G (2010) PTPL1/PTPN13 regulates breast cancer cell aggressiveness through direct inactivation of Src kinase. Cancer Res 70(12):5116–5126. https://doi.org/10.1158/0008-5472.CAN-09-4368

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  237. Yeh SH, Wu DC, Tsai CY, Kuo TJ, Yu WC, Chang YS, Chen CL, Chang CF, Chen DS, Chen PJ (2006) Genetic characterization of fas-associated phosphatase-1 as a putative tumor suppressor gene on chromosome 4q21.3 in hepatocellular carcinoma. Clin Cancer Res 12(4):1097–1108. https://doi.org/10.1158/1078-0432.CCR-05-1383

    Article  PubMed  CAS  Google Scholar 

  238. Deng J, Zhang J, Wang C, Wei Q, Zhou D, Zhao K (2016) Methylation and expression of PTPN22 in esophageal squamous cell carcinoma. Oncotarget 7(39):64043–64052. https://doi.org/10.18632/oncotarget.11581

    Article  PubMed  PubMed Central  Google Scholar 

  239. Negro R, Gobessi S, Longo PG, He Y, Zhang ZY, Laurenti L, Efremov DG (2012) Overexpression of the autoimmunity-associated phosphatase PTPN22 promotes survival of antigen-stimulated CLL cells by selectively activating AKT. Blood 119(26):6278–6287. https://doi.org/10.1182/blood-2012-01-403162

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  240. Horita Y, Ohashi K, Mukai M, Inoue M, Mizuno K (2008) Suppression of the invasive capacity of rat ascites hepatoma cells by knockdown of Slingshot or LIM kinase. J Biol Chem 283(10):6013–6021. https://doi.org/10.1074/jbc.M706538200

    Article  PubMed  CAS  Google Scholar 

  241. Wang Y, Kuramitsu Y, Kitagawa T, Baron B, Yoshino S, Maehara S, Maehara Y, Oka M, Nakamura K (2015) Cofilin-phosphatase slingshot-1L (SSH1L) is over-expressed in pancreatic cancer (PC) and contributes to tumor cell migration. Cancer Lett 360(2):171–176. https://doi.org/10.1016/j.canlet.2015.02.015

    Article  PubMed  CAS  Google Scholar 

  242. Mizuno K (2013) Signaling mechanisms and functional roles of cofilin phosphorylation and dephosphorylation. Cell Signal 25(2):457–469. https://doi.org/10.1016/j.cellsig.2012.11.001

    Article  PubMed  CAS  Google Scholar 

  243. Bassermann F, Frescas D, Guardavaccaro D, Busino L, Peschiaroli A, Pagano M (2008) The Cdc14B-Cdh1-Plk1 axis controls the G2 DNA-damage-response checkpoint. Cell 134(2):256–267. https://doi.org/10.1016/j.cell.2008.05.043

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  244. Lucci MA, Orlandi R, Triulzi T, Tagliabue E, Balsari A, Villa-Moruzzi E (2010) Expression profile of tyrosine phosphatases in HER2 breast cancer cells and tumors. Cell Oncol 32(5–6):361–372. https://doi.org/10.3233/CLO-2010-0520

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  245. Chen Q, Chen K, Guo G, Li F, Chen C, Wang S, Nalepa G, Huang S, Chen JL (2014) A critical role of CDKN3 in Bcr-Abl-mediated tumorigenesis. PLoS One 9(10):e111611. https://doi.org/10.1371/journal.pone.0111611

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  246. Nalepa G, Barnholtz-Sloan J, Enzor R, Dey D, He Y, Gehlhausen JR, Lehmann AS, Park SJ, Yang Y, Yang X, Chen S, Guan X, Chen Y, Renbarger J, Yang FC, Parada LF, Clapp W (2013) The tumor suppressor CDKN3 controls mitosis. J Cell Biol 201(7):997–1012. https://doi.org/10.1083/jcb.201205125

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  247. Fan C, Chen L, Huang Q, Shen T, Welsh EA, Teer JK, Cai J, Cress WD, Wu J (2015) Overexpression of major CDKN3 transcripts is associated with poor survival in lung adenocarcinoma. Br J Cancer 113(12):1735–1743. https://doi.org/10.1038/bjc.2015.378

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  248. Zang X, Chen M, Zhou Y, Xiao G, Xie Y, Wang X (2015) Identifying CDKN3 gene expression as a prognostic biomarker in lung adenocarcinoma via meta-analysis. Cancer Inform 14(Suppl 2):183–191. https://doi.org/10.4137/CIN.S17287

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  249. Yin Y, Shen WH (2008) PTEN: a new guardian of the genome. Oncogene 27(41):5443–5453. https://doi.org/10.1038/onc.2008.241

    Article  PubMed  CAS  Google Scholar 

  250. Weidner P, Sohn M, Gutting T, Friedrich T, Gaiser T, Magdeburg J, Kienle P, Ruh H, Hopf C, Behrens HM, Rocken C, Hanoch T, Seger R, Ebert MP, Burgermeister E (2016) Myotubularin-related protein 7 inhibits insulin signaling in colorectal cancer. Oncotarget 7(31):50490–50506. https://doi.org/10.18632/oncotarget.10466

    Article  PubMed  PubMed Central  Google Scholar 

  251. Yoo YD, Cho SM, Kim JS, Chang YS, Ahn CM, Kim HJ (2004) The human myotubularin-related protein suppresses the growth of lung carcinoma cells. Oncol Rep 12(3):667–671

    PubMed  CAS  Google Scholar 

  252. Kuo YZ, Tai YH, Lo HI, Chen YL, Cheng HC, Fang WY, Lin SH, Yang CL, Tsai ST, Wu LW (2014) MiR-99a exerts anti-metastasis through inhibiting myotubularin-related protein 3 expression in oral cancer. Oral Dis 20(3):e65–e75. https://doi.org/10.1111/odi.12133

    Article  PubMed  CAS  Google Scholar 

  253. Zheng B, Yu X, Chai R (2014) Myotubularin-related phosphatase 3 promotes growth of colorectal cancer cells. Sci World J 2014:703804. https://doi.org/10.1155/2014/703804

    Article  CAS  Google Scholar 

  254. Wang C, Feng Z, Jiang K, Zuo X (2017) Upregulation of MicroRNA-935 promotes the malignant behaviors of pancreatic carcinoma PANC-1 cells via targeting inositol polyphosphate 4-phosphatase type I gene (INPP4A). Oncol Res 25(4):559–569. https://doi.org/10.3727/096504016X14759554689565

    Article  PubMed  Google Scholar 

  255. Alho I, Costa L, Bicho M, Coelho C (2013) The role of low-molecular-weight protein tyrosine phosphatase (LMW-PTP ACP1) in oncogenesis. Tumour Biol 34(4):1979–1989. https://doi.org/10.1007/s13277-013-0784-1

    Article  PubMed  CAS  Google Scholar 

  256. Boutros R, Lobjois V, Ducommun B (2007) CDC25 phosphatases in cancer cells: key players? Good targets? Nat Rev Cancer 7(7):495–507. https://doi.org/10.1038/nrc2169

    Article  PubMed  CAS  Google Scholar 

  257. Sur S, Agrawal DK (2016) Phosphatases and kinases regulating CDC25 activity in the cell cycle: clinical implications of CDC25 overexpression and potential treatment strategies. Mol Cell Biochem 416(1–2):33–46. https://doi.org/10.1007/s11010-016-2693-2

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  258. Lee ST, Feng M, Wei Y, Li Z, Qiao Y, Guan P, Jiang X, Wong CH, Huynh K, Wang J, Li J, Karuturi KM, Tan EY, Hoon DS, Kang Y, Yu Q (2013) Protein tyrosine phosphatase UBASH3B is overexpressed in triple-negative breast cancer and promotes invasion and metastasis. Proc Natl Acad Sci USA 110(27):11121–11126. https://doi.org/10.1073/pnas.1300873110

    Article  PubMed  PubMed Central  Google Scholar 

  259. Morita K, Saitoh M, Tobiume K, Matsuura H, Enomoto S, Nishitoh H, Ichijo H (2001) Negative feedback regulation of ASK1 by protein phosphatase 5 (PP5) in response to oxidative stress. EMBO J 20(21):6028–6036. https://doi.org/10.1093/emboj/20.21.6028

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  260. Luo W, Peterson A, Garcia BA, Coombs G, Kofahl B, Heinrich R, Shabanowitz J, Hunt DF, Yost HJ, Virshup DM (2007) Protein phosphatase 1 regulates assembly and function of the beta-catenin degradation complex. EMBO J 26(6):1511–1521. https://doi.org/10.1038/sj.emboj.7601607

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  261. Kumar AS, Naruszewicz I, Wang P, Leung-Hagesteijn C, Hannigan GE (2004) ILKAP regulates ILK signaling and inhibits anchorage-independent growth. Oncogene 23(19):3454–3461. https://doi.org/10.1038/sj.onc.1207473

    Article  PubMed  CAS  Google Scholar 

  262. Leung-Hagesteijn C, Mahendra A, Naruszewicz I, Hannigan GE (2001) Modulation of integrin signal transduction by ILKAP, a protein phosphatase 2C associating with the integrin-linked kinase, ILK1. EMBO J 20(9):2160–2170. https://doi.org/10.1093/emboj/20.9.2160

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  263. Shan C, Kang HB, Elf S, Xie J, Gu TL, Aguiar M, Lonning S, Hitosugi T, Chung TW, Arellano M, Khoury HJ, Shin DM, Khuri FR, Boggon TJ, Fan J (2014) Tyr-94 phosphorylation inhibits pyruvate dehydrogenase phosphatase 1 and promotes tumor growth. J Biol Chem 289(31):21413–21422. https://doi.org/10.1074/jbc.M114.581124

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  264. Prabhu A, Sarcar B, Miller CR, Kim SH, Nakano I, Forsyth P, Chinnaiyan P (2015) RAS-mediated modulation of pyruvate dehydrogenase activity regulates mitochondrial reserve capacity and contributes to glioblastoma tumorigenesis. Neuro Oncol 17(9):1220–1230. https://doi.org/10.1093/neuonc/nou369

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  265. Cheng A, Kaldis P, Solomon MJ (2000) Dephosphorylation of human cyclin-dependent kinases by protein phosphatase type 2C alpha and beta 2 isoforms. J Biol Chem 275(44):34744–34749. https://doi.org/10.1074/jbc.M006210200

    Article  PubMed  CAS  Google Scholar 

  266. Wang H, Chen Y, Han J, Meng Q, Xi Q, Wu G, Zhang B (2016) DCAF4L2 promotes colorectal cancer invasion and metastasis via mediating degradation of NFkappab negative regulator PPM1B. Am J Transl Res 8(2):405–418

    PubMed  PubMed Central  CAS  Google Scholar 

  267. Geng J, Fan J, Ouyang Q, Zhang X, Zhang X, Yu J, Xu Z, Li Q, Yao X, Liu X, Zheng J (2014) Loss of PPM1A expression enhances invasion and the epithelial-to-mesenchymal transition in bladder cancer by activating the TGF-beta/Smad signaling pathway. Oncotarget 5(14):5700–5711. https://doi.org/10.18632/oncotarget.2144

    Article  PubMed  PubMed Central  Google Scholar 

  268. Strovel ET, Wu D, Sussman DJ (2000) Protein phosphatase 2Calpha dephosphorylates axin and activates LEF-1-dependent transcription. J Biol Chem 275(4):2399–2403

    Article  PubMed  CAS  Google Scholar 

  269. Koh CG, Tan EJ, Manser E, Lim L (2002) The p21-activated kinase PAK is negatively regulated by POPX1 and POPX2, a pair of serine/threonine phosphatases of the PP2C family. Curr Biol 12(4):317–321

    Article  PubMed  CAS  Google Scholar 

  270. Chen MB, Liu YY, Cheng LB, Lu JW, Zeng P, Lu PH (2017) AMPKalpha phosphatase Ppm1E upregulation in human gastric cancer is required for cell proliferation. Oncotarget 8(19):31288–31296. https://doi.org/10.18632/oncotarget.16126

    Article  PubMed  PubMed Central  Google Scholar 

  271. Lee-Hoeflich ST, Pham TQ, Dowbenko D, Munroe X, Lee J, Li L, Zhou W, Haverty PM, Pujara K, Stinson J, Chan SM, Eastham-Anderson J, Pandita A, Seshagiri S, Hoeflich KP, TuRAShvili G, Gelmon KA, Aparicio SA, Davis DP, Sliwkowski MX, Stern HM (2011) PPM1H is a p27 phosphatase implicated in trastuzumab resistance. Cancer Discov 1(4):326–337. https://doi.org/10.1158/2159-8290.CD-11-0062

    Article  PubMed  CAS  Google Scholar 

  272. Shen T, Sun C, Zhang Z, Xu N, Duan X, Feng XH, Lin X (2014) Specific control of BMP signaling and mesenchymal differentiation by cytoplasmic phosphatase PPM1H. Cell Res 24(6):727–741. https://doi.org/10.1038/cr.2014.48

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  273. Sugiura T, Noguchi Y, Sakurai K, Hattori C (2008) Protein phosphatase 1H, overexpressed in colon adenocarcinoma, is associated with CSE1L. Cancer Biol Ther 7(2):285–292

    Article  PubMed  CAS  Google Scholar 

  274. Zhu H, Qin H, Li DM, Liu J, Zhao Q (2016) Effect of PPM1H on malignant phenotype of human pancreatic cancer cells. Oncol Rep 36(5):2926–2934. https://doi.org/10.3892/or.2016.5065

    Article  PubMed  CAS  Google Scholar 

  275. Sun T, Fu J, Shen T, Lin X, Liao L, Feng XH, Xu J (2016) The small C-terminal domain phosphatase 1 inhibits cancer cell migration and invasion by dephosphorylating Ser(P)68-Twist1 to accelerate Twist1 protein degradation. J Biol Chem 291(22):11518–11528. https://doi.org/10.1074/jbc.M116.721795

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  276. Wu Y, Evers BM, Zhou BP (2009) Small C-terminal domain phosphatase enhances snail activity through dephosphorylation. J Biol Chem 284(1):640–648. https://doi.org/10.1074/jbc.M806916200

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Case Western Reserve University, Cleveland, OH, USA

    Goutham Narla & Christopher B. Ryder

  2. Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Jaya Sangodkar

Authors
  1. Goutham Narla
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jaya Sangodkar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christopher B. Ryder
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Christopher B. Ryder.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Narla, G., Sangodkar, J. & Ryder, C.B. The impact of phosphatases on proliferative and survival signaling in cancer. Cell. Mol. Life Sci. 75, 2695–2718 (2018). https://doi.org/10.1007/s00018-018-2826-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-018-2826-8

Keywords

Search

Navigation