Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

The regulatory roles of phosphatases in cancer

Oncogene volume 33, pages 939–953 (2014)Cite this article

Subjects

Abstract

The relevance of potentially reversible post-translational modifications required for controlling cellular processes in cancer is one of the most thriving arenas of cellular and molecular biology. Any alteration in the balanced equilibrium between kinases and phosphatases may result in development and progression of various diseases, including different types of cancer, though phosphatases are relatively under-studied. Loss of phosphatases such as PTEN (phosphatase and tensin homologue deleted on chromosome 10), a known tumour suppressor, across tumour types lends credence to the development of phosphatidylinositol 3—kinase inhibitors alongside the use of phosphatase expression as a biomarker, though phase 3 trial data are lacking. In this review, we give an updated report on phosphatase dysregulation linked to organ-specific malignancies.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

References

  1. Zhou YA, Zhang T, Zhao JB, Wang XP, Jiang T, Gu ZP et al. The adenovirus-mediated transfer of PTEN inhibits the growth of esophageal cancer cells in vitro and in vivo. Biosci Biotechnol Biochem 2010; 74: 736–740.

    Article  CAS  PubMed  Google Scholar 

  2. Hou G, Lu Z, Liu M, Liu H, Xue L . Mutational analysis of the PTEN gene and its effects in esophageal squamous cell carcinoma. Dig Dis Sci 2011; 56: 1315–1322.

    Article  CAS  PubMed  Google Scholar 

  3. Ma J, Zhang J, Ning T, Chen Z, Xu C . Association of genetic polymorphisms in MDM2, PTEN and P53 with risk of esophageal squamous cell carcinoma. J Hum Genet 2012; 57: 261–264.

    Article  CAS  PubMed  Google Scholar 

  4. Nishioka K, Doki Y, Shiozaki H, Yamamoto H, Tamura S, Yasuda T et al. Clinical significance of CDC25A and CDC25B expression in squamous cell carcinomas of the oesophagus. Br J Cancer 2001; 85: 412–421.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Dong J, Zeng BH, Xu LH, Wang JY, Li MZ, Zeng MS et al. Anti-CDC25B autoantibody predicts poor prognosis in patients with advanced esophageal squamous cell carcinoma. J Transl Med 2010; 8: 81.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Cao X, Li Y, Luo RZ, He LR, Yang J, Zeng MS et al. Tyrosine-protein phosphatase nonreceptor type 12 is a novel prognostic biomarker for esophageal squamous cell carcinoma. Ann Thorac Surg 2012; 93: 1674–1680.

    Article  PubMed  Google Scholar 

  7. You YJ, Chen YP, Zheng XX, Meltzer SJ, Zhang H . Aberrant methylation of the PTPRO gene in peripheral blood as a potential biomarker in esophageal squamous cell carcinoma patients. Cancer Lett 2012; 315: 138–144.

    Article  CAS  PubMed  Google Scholar 

  8. Motiwala T, Majumder S, Kutay H, Smith DS, Neuberg DS, Lucas DM et al. Methylation and silencing of protein tyrosine phosphatase receptor type O in chronic lymphocytic leukemia. Clin Cancer Res 2007; 13: 3174–3181.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Hatakeyama M . Helicobacter pylori and gastric carcinogenesis. J Gastroenterol 2009; 44: 239–248.

    Article  CAS  PubMed  Google Scholar 

  10. Yamazaki S, Yamakawa A, Ito Y, Ohtani M, Higashi H, Hatakeyama M et al. The CagA protein of Helicobacter pylori is translocated into epithelial cells and binds to SHP-2 in human gastric mucosa. J Infect Dis 2003; 187: 334–337.

    Article  CAS  PubMed  Google Scholar 

  11. Chan G, Kalaitzidis D, Neel BG . The tyrosine phosphatase Shp2 (PTPN11) in cancer. Cancer Metastasis Rev 2008; 27: 179–192.

    Article  CAS  PubMed  Google Scholar 

  12. Kim JS, Shin OR, Kim HK, Cho YS, An CH, Lim KW et al. Overexpression of protein phosphatase non-receptor type 11 (PTPN11) in gastric carcinomas. Dig Dis Sci 2010; 55: 1565–1569.

    Article  CAS  PubMed  Google Scholar 

  13. Shin CM, Kim N, Park JH, Kang GH, Kim JS, Jung HC et al. Prediction of the risk for gastric cancer using candidate methylation markers in the non-neoplastic gastric mucosae. J Pathol 2012; 226: 654–665.

    Article  CAS  PubMed  Google Scholar 

  14. Ksiaa F, Ziadi S, Amara K, Korbi S, Trimeche M . Biological significance of promoter hypermethylation of tumor-related genes in patients with gastric carcinoma. Clin Chim Acta 2009; 404: 128–133.

    Article  CAS  PubMed  Google Scholar 

  15. Yang SH, Seo MY, Jeong HJ, Jeung HC, Shin J, Kim SC et al. Gene copy number change events at chromosome 20 and their association with recurrence in gastric cancer patients. Clin Cancer Res 2005; 11 (2 Pt 1): 612–620.

    CAS  PubMed  Google Scholar 

  16. Wang J, Liu B, Chen X, Su L, Wu P, Wu J et al. PTP1B expression contributes to gastric cancer progression. Med Oncol 2012; 29: 948–956.

    Article  CAS  PubMed  Google Scholar 

  17. Lessard L, Stuible M, Tremblay ML . The two faces of PTP1B in cancer. Biochim Biophys Acta 2010; 1804: 613–619.

    Article  CAS  PubMed  Google Scholar 

  18. Wu CW, Chen JH, Kao HL, Li AF, Lai CH, Chi CW et al. PTPN3 and PTPN4 tyrosine phosphatase expression in human gastric adenocarcinoma. Anticancer Res 2006; 26: 1643–1649.

    CAS  PubMed  Google Scholar 

  19. Hou SW, Zhi HY, Pohl N, Loesch M, Qi XM, Li RS et al. PTPH1 dephosphorylates and cooperates with p38gamma MAPK to increase ras oncogenesis through PDZ-mediated interaction. Cancer Res 2010; 70: 2901–2910.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Gu MX, York JD, Warshawsky I, Majerus PW . Identification, cloning, and expression of a cytosolic megakaryocyte protein-tyrosine-phosphatase with sequence homology to cytoskeletal protein 4.1. Proc Natl Acad Sci USA 1991; 88: 5867–5871.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Gu M, Meng K, Majerus PW . The effect of overexpression of the protein tyrosine phosphatase PTPMEG on cell growth and on colony formation in soft agar in COS-7 cells. Proc Natl Acad Sci USA 1996; 93: 12980–12985.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wu CW, Kao HL, Li AF, Chi CW, Lin WC . Protein tyrosine-phosphatase expression profiling in gastric cancer tissues. Cancer Lett 2006; 242: 95–103.

    Article  CAS  PubMed  Google Scholar 

  23. Zeng L, Si X, Yu WP, Le HT, Ng KP, Teng RM et al. PTP alpha regulates integrin-stimulated FAK autophosphorylation and cytoskeletal rearrangement in cell spreading and migration. J Cell Biol 2003; 160: 137–146.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Pallen CJ . Protein tyrosine phosphatase alpha (PTPalpha): a Src family kinase activator and mediator of multiple biological effects. Curr Top Med Chem 2003; 3: 821–835.

    Article  CAS  PubMed  Google Scholar 

  25. Harder KW, Moller NP, Peacock JW, Jirik FR . Protein-tyrosine phosphatase alpha regulates Src family kinases and alters cell-substratum adhesion. J Biol Chem 1998; 273: 31890–31900.

    Article  CAS  PubMed  Google Scholar 

  26. Wang JF, Dai DQ . Metastatic suppressor genes inactivated by aberrant methylation in gastric cancer. World J Gastroenterol 2007; 13: 5692–5698.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wang Z, Shen D, Parsons DW, Bardelli A, Sager J, Szabo S et al. Mutational analysis of the tyrosine phosphatome in colorectal cancers. Science 2004; 304: 1164–1166.

    Article  CAS  PubMed  Google Scholar 

  28. Lee JW, Jeong EG, Lee SH, Nam SW, Kim SH, Lee JY et al. Mutational analysis of PTPRT phosphatase domains in common human cancers. APMIS 2007; 115: 47–51.

    Article  CAS  PubMed  Google Scholar 

  29. Matozaki T, Suzuki T, Uchida T, Inazawa J, Ariyama T, Matsuda K et al. Molecular cloning of a human transmembrane-type protein tyrosine phosphatase and its expression in gastrointestinal cancers. J Biol Chem 1994; 269: 2075–2081.

    Article  CAS  PubMed  Google Scholar 

  30. Bang YJ, Kwon JH, Kang SH, Kim JW, Yang YC . Increased MAPK activity and MKP-1 overexpression in human gastric adenocarcinoma. Biochem Biophys Res Commun 1998; 250: 43–47.

    Article  CAS  PubMed  Google Scholar 

  31. Miskad UA, Semba S, Kato H, Yokozaki H . Expression of PRL-3 phosphatase in human gastric carcinomas: close correlation with invasion and metastasis. Pathobiology 2004; 71: 176–184.

    Article  CAS  PubMed  Google Scholar 

  32. Miskad UA, Semba S, Kato H, Matsukawa Y, Kodama Y, Mizuuchi E et al. High PRL-3 expression in human gastric cancer is a marker of metastasis and grades of malignancies: an in situ hybridization study. Virchows Arch 2007; 450: 303–310.

    Article  CAS  PubMed  Google Scholar 

  33. Wang Z, Cai SR, He YL, Zhan WH, Chen CQ, Cui J et al. High expression of PRL-3 can promote growth of gastric cancer and exhibits a poor prognostic impact on patients. Ann Surg Oncol 2009; 16: 208–219.

    Article  PubMed  Google Scholar 

  34. Li ZR, Wang Z, Zhu BH, He YL, Peng JS, Cai SR et al. Association of tyrosine PRL-3 phosphatase protein expression with peritoneal metastasis of gastric carcinoma and prognosis. Surg Today 2007; 37: 646–651.

    Article  CAS  PubMed  Google Scholar 

  35. Dai N, Lu AP, Shou CC, Li JY . Expression of phosphatase regenerating liver 3 is an independent prognostic indicator for gastric cancer. World J Gastroenterol 2009; 15: 1499–1505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Ooki A, Yamashita K, Kikuchi S, Sakuramoto S, Katada N, Waraya M et al. Therapeutic potential of PRL-3 targeting and clinical significance of PRL-3 genomic amplification in gastric cancer. BMC Cancer 2011; 11: 122.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Korff S, Woerner SM, Yuan YP, Bork P, von Knebel Doeberitz M, Gebert J . Frameshift mutations in coding repeats of protein tyrosine phosphatase genes in colorectal tumors with microsatellite instability. BMC Cancer 2008; 8: 329.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Mori Y, Yin J, Sato F, Sterian A, Simms LA, Selaru FM et al. Identification of genes uniquely involved in frequent microsatellite instability colon carcinogenesis by expression profiling combined with epigenetic scanning. Cancer Res 2004; 64: 2434–2438.

    Article  CAS  PubMed  Google Scholar 

  39. Sato T, Irie S, Kitada S, Reed JC . FAP-1: a protein tyrosine phosphatase that associates with Fas. Science 1995; 268: 411–415.

    Article  CAS  PubMed  Google Scholar 

  40. Miyazaki T, Atarashi Y, Yasumura S, Minatoya I, Ogawa K, Iwamoto M et al. Fas-associated phosphatase-1 promotes Fas-mediated apoptosis in human colon cancer cells: novel function of FAP-1. J Gastroenterol Hepatol 2006; 21 (1 Pt 1): 84–91.

    Article  CAS  PubMed  Google Scholar 

  41. Yao H, Song E, Chen J, Hamar P . Expression of FAP-1 by human colon adenocarcinoma: implication for resistance against Fas-mediated apoptosis in cancer. Br J Cancer 2004; 91: 1718–1725.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Lassmann S, Weis R, Makowiec F, Roth J, Danciu M, Hopt U et al. Array CGH identifies distinct DNA copy number profiles of oncogenes and tumor suppressor genes in chromosomal- and microsatellite-unstable sporadic colorectal carcinomas. J Mol Med (Berl) 2007; 85: 293–304.

    Article  CAS  Google Scholar 

  43. Zhu S, Bjorge JD, Fujita DJ . PTP1B contributes to the oncogenic properties of colon cancer cells through Src activation. Cancer Res 2007; 67: 10129–10137.

    Article  CAS  PubMed  Google Scholar 

  44. Corvinus FM, Orth C, Moriggl R, Tsareva SA, Wagner S, Pfitzner EB et al. Persistent STAT3 activation in colon cancer is associated with enhanced cell proliferation and tumor growth. Neoplasia 2005; 7: 545–555.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Lin Q, Lai R, Chirieac LR, Li C, Thomazy VA, Grammatikakis I et al. Constitutive activation of JAK3/STAT3 in colon carcinoma tumors and cell lines: inhibition of JAK3/STAT3 signaling induces apoptosis and cell cycle arrest of colon carcinoma cells. Am J Pathol 2005; 167: 969–980.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Zhang X, Guo A, Yu J, Possemato A, Chen Y, Zheng W et al. Identification of STAT3 as a substrate of receptor protein tyrosine phosphatase T. Proc Natl Acad Sci USA 2007; 104: 4060–4064.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Veeriah S, Brennan C, Meng S, Singh B, Fagin JA, Solit DB et al. The tyrosine phosphatase PTPRD is a tumor suppressor that is frequently inactivated and mutated in glioblastoma and other human cancers. Proc Natl Acad Sci USA 2009; 106: 9435–9440.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Zhao Y, Zhang X, Guda K, Lawrence E, Sun Q, Watanabe T et al. Identification and functional characterization of paxillin as a target of protein tyrosine phosphatase receptor T. Proc Natl Acad Sci USA 2010; 107: 2592–2597.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Sjöblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD et al. The consensus coding sequences of human breast and colorectal cancers. Science 2006; 314: 268–274.

    Article  CAS  PubMed  Google Scholar 

  50. Funato K, Yamazumi Y, Oda T, Akiyama T . Tyrosine phosphatase PTPRD suppresses colon cancer cell migration in coordination with CD44. Exp Ther Med 2011; 2: 457–463.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Tabiti K, Smith DR, Goh HS, Pallen CJ . Increased mRNA expression of the receptor-like protein tyrosine phosphatase alpha in late stage colon carcinomas. Cancer Lett 1995; 93: 239–248.

    Article  CAS  PubMed  Google Scholar 

  52. Krndija D, Schmid H, Eismann JL, Lother U, Adler G, Oswald F et al. Substrate stiffness and the receptor-type tyrosine-protein phosphatase alpha regulate spreading of colon cancer cells through cytoskeletal contractility. Oncogene 2010; 29: 2724–2738.

    Article  CAS  PubMed  Google Scholar 

  53. Zheng X, Resnick RJ, Shalloway D . Apoptosis of estrogen-receptor negative breast cancer and colon cancer cell lines by PTP alpha and src RNAi. Int J Cancer 2008; 122: 1999–2007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Seo Y, Matozaki T, Tsuda M, Hayashi Y, Itoh H, Kasuga M . Overexpression of SAP-1, a transmembrane-type protein tyrosine phosphatase, in human colorectal cancers. Biochem Biophys Res Commun 1997; 231: 705–711.

    Article  CAS  PubMed  Google Scholar 

  55. Sadakata H, Okazawa H, Sato T, Supriatna Y, Ohnishi H, Kusakari S et al. SAP-1 is a microvillus-specific protein tyrosine phosphatase that modulates intestinal tumorigenesis. Genes Cells 2009; 14: 295–308.

    Article  CAS  PubMed  Google Scholar 

  56. Malentacchi F, Marzocchini R, Gelmini S, Orlando C, Serio M, Ramponi G et al. Up-regulated expression of low molecular weight protein tyrosine phosphatases in different human cancers. Biochem Biophys Res Commun 2005; 334: 875–883.

    Article  CAS  PubMed  Google Scholar 

  57. Chiarugi P, Taddei ML, Schiavone N, Papucci L, Giannoni E, Fiaschi T et al. LMW-PTP is a positive regulator of tumor onset and growth. Oncogene 2004; 23: 3905–3914.

    Article  CAS  PubMed  Google Scholar 

  58. Mollevi DG, Aytes A, Padulles L, Martinez-Iniesta M, Baixeras N, Salazar R et al. PRL-3 is essentially overexpressed in primary colorectal tumours and associates with tumour aggressiveness. Br J Cancer 2008; 99: 1718–1725.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Saha S, Bardelli A, Buckhaults P, Velculescu VE, Rago C, Croix B et al. A phosphatase associated with metastasis of colorectal cancer. Science 2001; 294: 1343–1346.

    Article  CAS  PubMed  Google Scholar 

  60. Jiang Y, Liu XQ, Rajput A, Geng L, Ongchin M, Zeng Q et al. Phosphatase PRL-3 is a direct regulatory target of TGFbeta in colon cancer metastasis. Cancer Res 2011; 71: 234–244.

    Article  CAS  PubMed  Google Scholar 

  61. Wang H, Quah SY, Dong JM, Manser E, Tang JP, Zeng Q . PRL-3 down-regulates PTEN expression and signals through PI3K to promote epithelial-mesenchymal transition. Cancer Res 2007; 67: 2922–2926.

    Article  CAS  PubMed  Google Scholar 

  62. Ruivenkamp C, Hermsen M, Postma C, Klous A, Baak J, Meijer G et al. LOH of PTPRJ occurs early in colorectal cancer and is associated with chromosomal loss of 18q12-21. Oncogene 2003; 22: 3472–3474.

    Article  CAS  PubMed  Google Scholar 

  63. Balavenkatraman KK, Jandt E, Friedrich K, Kautenburger T, Pool-Zobel BL, Ostman A et al. DEP-1 protein tyrosine phosphatase inhibits proliferation and migration of colon carcinoma cells and is upregulated by protective nutrients. Oncogene 2006; 25: 6319–6324.

    Article  CAS  PubMed  Google Scholar 

  64. Lin MS, Huang JX, Chen WC, Zhang BF, Fang J, Zhou Q et al. Expression of PPARgamma and PTEN in human colorectal cancer: an immunohistochemical study using tissue microarray methodology. Oncol Lett 2011; 2: 1219–1224.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Loda M, Capodieci P, Mishra R, Yao H, Corless C, Grigioni W et al. Expression of mitogen-activated protein kinase phosphatase-1 in the early phases of human epithelial carcinogenesis. Am J Pathol 1996; 149: 1553–1564.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Montagut C, Arumi MIM, Bellosillo B, Gallen M, Martinez-Fernandez A, Martinez-Aviles L et al. Mitogen-activated protein kinase phosphatase-1 (MKP-1) impairs the response to anti-epidermal growth factor receptor (EGFR) antibody cetuximab in metastatic colorectal cancer patients. Br J Cancer 2010; 102: 1137–1144.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Ruivenkamp CA, van Wezel T, Zanon C, Stassen AP, Vlcek C, Csikos T et al. Ptprj is a candidate for the mouse colon-cancer susceptibility locus Scc1 and is frequently deleted in human cancers. Nat Genet 2002; 31: 295–300.

    Article  CAS  PubMed  Google Scholar 

  68. Cheng JQ, Ruggeri B, Klein WM, Sonoda G, Altomare DA, Watson DK et al. Amplification of AKT2 in human pancreatic cells and inhibition of AKT2 expression and tumorigenicity by antisense RNA. Proc Natl Acad Sci USA 1996; 93: 3636–3641.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Schild C, Wirth M, Reichert M, Schmid RM, Saur D, Schneider G . PI3K signaling maintains c-myc expression to regulate transcription of E2F1 in pancreatic cancer cells. Mol Carcinog 2009; 48: 1149–1158.

    Article  CAS  PubMed  Google Scholar 

  70. Pham NA, Schwock J, Iakovlev V, Pond G, Hedley DW, Tsao MS . Immunohistochemical analysis of changes in signaling pathway activation downstream of growth factor receptors in pancreatic duct cell carcinogenesis. BMC Cancer 2008; 8: 43.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Nitsche C, Edderkaoui M, Moore RM, Eibl G, Kasahara N, Treger J et al. The phosphatase PHLPP1 regulates Akt2, promotes pancreatic cancer cell death, and inhibits tumor formation. Gastroenterology 2012; 142: 377–387 e1-5.

    Article  CAS  PubMed  Google Scholar 

  72. Gao T, Furnari F, Newton AC . PHLPP: a phosphatase that directly dephosphorylates Akt, promotes apoptosis, and suppresses tumor growth. Mol Cell 2005; 18: 13–24.

    Article  CAS  PubMed  Google Scholar 

  73. Brognard J, Sierecki E, Gao T, Newton AC . PHLPP and a second isoform, PHLPP2, differentially attenuate the amplitude of Akt signaling by regulating distinct Akt isoforms. Mol Cell 2007; 25: 917–931.

    Article  CAS  PubMed  Google Scholar 

  74. Okami K, Wu L, Riggins G, Cairns P, Goggins M, Evron E et al. Analysis of PTEN/MMAC1 alterations in aerodigestive tract tumors. Cancer Res 1998; 58: 509–511.

    CAS  PubMed  Google Scholar 

  75. Farrow B, Evers BM . Activation of PPARgamma increases PTEN expression in pancreatic cancer cells. Biochem Biophys Res Commun 2003; 301: 50–53.

    Article  CAS  PubMed  Google Scholar 

  76. Zhong H, Chiles K, Feldser D, Laughner E, Hanrahan C, Georgescu MM et al. Modulation of hypoxia-inducible factor 1alpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Res 2000; 60: 1541–1545.

    CAS  PubMed  Google Scholar 

  77. Stambolic V, Suzuki A, de la Pompa JL, Brothers GM, Mirtsos C, Sasaki T et al. Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell 1998; 95: 29–39.

    Article  CAS  PubMed  Google Scholar 

  78. Chow JY, Dong H, Quach KT, Van Nguyen PN, Chen K, Carethers JM . TGF-beta mediates PTEN suppression and cell motility through calcium-dependent PKC-alpha activation in pancreatic cancer cells. Am J Physiol Gastrointest Liver Physiol 2008; 294: G899–G905.

    Article  CAS  PubMed  Google Scholar 

  79. Chow JY, Ban M, Wu HL, Nguyen F, Huang M, Chung H et al. TGF-beta downregulates PTEN via activation of NF-kappaB in pancreatic cancer cells. Am J Physiol Gastrointest Liver Physiol 2010; 298: G275–G282.

    Article  CAS  PubMed  Google Scholar 

  80. Maurice D, Pierreux CE, Howell M, Wilentz RE, Owen MJ, Hill CS . Loss of Smad4 function in pancreatic tumors: C-terminal truncation leads to decreased stability. J Biol Chem 2001; 276: 43175–43181.

    Article  CAS  PubMed  Google Scholar 

  81. Antonello D, Moore PS, Zamboni G, Falconi M, Scarpa A . Absence of mutations in the transforming growth factor-beta inducible early gene 1, TIEG1, in pancreatic cancer. Cancer Lett 2002; 183: 179–183.

    Article  CAS  PubMed  Google Scholar 

  82. Tascilar M, Skinner HG, Rosty C, Sohn T, Wilentz RE, Offerhaus GJ et al. The SMAD4 protein and prognosis of pancreatic ductal adenocarcinoma. Clin Cancer Res 2001; 7: 4115–4121.

    CAS  PubMed  Google Scholar 

  83. Feng XH, Derynck R . Specificity and versatility in tgf-beta signaling through Smads. Annu Rev Cell Dev Biol 2005; 21: 659–693.

    Article  CAS  PubMed  Google Scholar 

  84. Lin X, Duan X, Liang YY, Su Y, Wrighton KH, Long J et al. PPM1A functions as a Smad phosphatase to terminate TGFbeta signaling. Cell 2006; 125: 915–928.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Cejudo-Marin R, Tarrega C, Nunes-Xavier CE, Pulido R . Caspase-3 cleavage of DUSP6/MKP3 at the interdomain region generates active MKP3 fragments that regulate ERK1/2 subcellular localization and function. J Mol Biol 2012; 420: 128–138.

    Article  CAS  PubMed  Google Scholar 

  86. Furukawa T, Sunamura M, Motoi F, Matsuno S, Horii A . Potential tumor suppressive pathway involving DUSP6/MKP-3 in pancreatic cancer. Am J Pathol 2003; 162: 1807–1815.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Furukawa T, Yatsuoka T, Youssef EM, Abe T, Yokoyama T, Fukushige S et al. Genomic analysis of DUSP6, a dual specificity MAP kinase phosphatase, in pancreatic cancer. Cytogenet Cell Genet 1998; 82: 156–159.

    Article  CAS  PubMed  Google Scholar 

  88. Furukawa T, Fujisaki R, Yoshida Y, Kanai N, Sunamura M, Abe T et al. Distinct progression pathways involving the dysfunction of DUSP6/MKP-3 in pancreatic intraepithelial neoplasia and intraductal papillary-mucinous neoplasms of the pancreas. Mod Pathol 2005; 18: 1034–1042.

    Article  CAS  PubMed  Google Scholar 

  89. Wang W, Abbruzzese JL, Evans DB, Larry L, Cleary KR, Chiao PJ . The nuclear factor-kappa B RelA transcription factor is constitutively activated in human pancreatic adenocarcinoma cells. Clin Cancer Res 1999; 5: 119–127.

    CAS  PubMed  Google Scholar 

  90. DiDonato JA, Hayakawa M, Rothwarf DM, Zandi E, Karin M . A cytokine-responsive IkappaB kinase that activates the transcription factor NF-kappaB. Nature 1997; 388: 548–554.

    Article  CAS  PubMed  Google Scholar 

  91. Kray AE, Carter RS, Pennington KN, Gomez RJ, Sanders LE, Llanes JM et al. Positive regulation of IkappaB kinase signaling by protein serine/threonine phosphatase 2A. J Biol Chem 2005; 280: 35974–35982.

    Article  CAS  PubMed  Google Scholar 

  92. Li W, Chen Z, Zong Y, Gong F, Zhu Y, Lv J et al. PP2A inhibitors induce apoptosis in pancreatic cancer cell line PANC-1 through persistent phosphorylation of IKKalpha and sustained activation of the NF-kappaB pathway. Cancer Lett 2011; 304: 117–127.

    Article  CAS  PubMed  Google Scholar 

  93. Li W, Chen Z, Gong FR, Zong Y, Chen K, Li DM et al. Growth of the pancreatic cancer cell line PANC-1 is inhibited by protein phosphatase 2A inhibitors through overactivation of the c-Jun N-terminal kinase pathway. Eur J Cancer 2011; 47: 2654–2664.

    Article  CAS  PubMed  Google Scholar 

  94. Muller P, Henn W, Niedermayer I, Ketter R, Feiden W, Steudel WI et al. Deletion of chromosome 1p and loss of expression of alkaline phosphatase indicate progression of meningiomas. Clin Cancer Res 1999; 5: 3569–3577.

    CAS  PubMed  Google Scholar 

  95. Kobayashi I, Shidara K, Okuno S, Yamada S, Imanishi Y, Mori K et al. Higher serum bone alkaline phosphatase as a predictor of mortality in male hemodialysis patients. Life Sci 2012; 90: 212–218.

    Article  CAS  PubMed  Google Scholar 

  96. Chuang YC, Lin AT, Chen KK, Chang YH, Chen MT, Chang LS . Paraneoplastic elevation of serum alkaline phosphatase in renal cell carcinoma: incidence and implication on prognosis. J Urol 1997; 158: 1684–1687.

    Article  CAS  PubMed  Google Scholar 

  97. Rajarubendra N, Bolton D, Lawrentschuk N . Diagnosis of bone metastases in urological malignancies—an update. Urology 2010; 76: 782–790.

    Article  PubMed  Google Scholar 

  98. Lavecchia A, Di Giovanni C, Novellino E . Inhibitors of Cdc25 phosphatases as anticancer agents: a patent review. Expert Opin Ther Patents 2010; 20: 405–425.

    Article  CAS  Google Scholar 

  99. Yu XY, Zhang Z, Zhang GJ, Guo KF, Kong CZ . Knockdown of Cdc25B in renal cell carcinoma is associated with decreased malignant features. Asian Pac J Cancer Prev 2012; 13: 931–935.

    Article  PubMed  Google Scholar 

  100. Mizuno R, Oya M, Hara S, Matsumoto M, Horiguchi A, Ohigashi T et al. Modulation of bcl-2 family proteins in MAPK independent apoptosis induced by a cdc25 phosphatase inhibitor Cpd 5 in renal cancer cells. Oncol Rep 2005; 14: 639–644.

    CAS  PubMed  Google Scholar 

  101. Castro ME, Ferrer I, Cascon A, Guijarro MV, Lleonart M, Ramon y Cajal S et al. PPP1CA contributes to the senescence program induced by oncogenic Ras. Carcinogenesis 2008; 29: 491–499.

    Article  CAS  PubMed  Google Scholar 

  102. Brems-Eskildsen AS, Zieger K, Toldbod H, Holcomb C, Higuchi R, Mansilla F et al. Prediction and diagnosis of bladder cancer recurrence based on urinary content of hTERT, SENP1, PPP1CA, and MCM5 transcripts. BMC Cancer 2010; 10: 646.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Carlucci A, Porpora M, Garbi C, Galgani M, Santoriello M, Mascolo M et al. PTPD1 supports receptor stability and mitogenic signaling in bladder cancer cells. J Biol Chem 2010; 285: 39260–39270.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Li X, Tan X, Yu Y, Chen H, Chang W, Hou J et al. D9S168 microsatellite alteration predicts a poor prognosis in patients with clear cell renal cell carcinoma and correlates with the down-regulation of protein tyrosine phosphatase receptor delta. Cancer 2011; 117: 4201–4211.

    Article  CAS  PubMed  Google Scholar 

  105. Shin Lee J, Seok Kim H, Bok Kim Y, Cheol Lee M, Soo Park C . Expression of PTEN in renal cell carcinoma and its relation to tumor behavior and growth. J Surg Oncol 2003; 84: 166–172.

    Article  PubMed  CAS  Google Scholar 

  106. Hager M, Haufe H, Kemmerling R, Mikuz G, Kolbitsch C, Moser PL . PTEN expression in renal cell carcinoma and oncocytoma and prognosis. Pathology 2007; 39: 482–485.

    Article  CAS  PubMed  Google Scholar 

  107. Hager M, Haufe H, Lusuardi L, Schmeller N, Kolbitsch C . PTEN, pAKT, and pmTOR expression and subcellular distribution in primary renal cell carcinomas and their metastases. Cancer Invest 2011; 29: 427–438.

    Article  CAS  PubMed  Google Scholar 

  108. Mundhenk J, Hennenlotter J, Zug L, Alloussi SH, Todenhoefer T, Gakis G et al. Evidence for PTEN-independent Akt activation and Akt-independent p27(Kip1) expression in advanced bladder cancer. Oncol Lett 2011; 2: 1089–1093.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Schneider E, Keppler R, Prawitt D, Steinwender C, Roos FC, Thuroff JW et al. Migration of renal tumor cells depends on dephosphorylation of Shc by PTEN. Int J Oncol 2011; 38: 823–831.

    CAS  PubMed  Google Scholar 

  110. Lin PY, Fosmire SP, Park SH, Park JY, Baksh S, Modiano JF et al. Attenuation of PTEN increases p21 stability and cytosolic localization in kidney cancer cells: a potential mechanism of apoptosis resistance. Mol Cancer 2007; 6: 16.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. Liu J, Babaian DC, Liebert M, Steck PA, Kagan J . Inactivation of MMAC1 in bladder transitional-cell carcinoma cell lines and specimens. Mol Carcinog 2000; 29: 143–150.

    Article  CAS  PubMed  Google Scholar 

  112. Puzio-Kuter AM, Castillo-Martin M, Kinkade CW, Wang X, Shen TH, Matos T et al. Inactivation of p53 and Pten promotes invasive bladder cancer. Genes Dev 2009; 23: 675–680.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Shorning BY, Griffiths D, Clarke AR . Lkb1 and Pten synergise to suppress mTOR-mediated tumorigenesis and epithelial-mesenchymal transition in the mouse bladder. PLoS One 2011; 6: e16209.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Lai MW, Chen TC, Pang ST, Yeh CT . Overexpression of cyclin-dependent kinase-associated protein phosphatase enhances cell proliferation in renal cancer cells. Urol Oncol 2012; 30: 871–878.

    Article  CAS  PubMed  Google Scholar 

  115. Mizuno R, Oya M, Shiomi T, Marumo K, Okada Y, Murai M . Inhibition of MKP-1 expression potentiates JNK related apoptosis in renal cancer cells. J Urol 2004; 172: 723–727.

    Article  CAS  PubMed  Google Scholar 

  116. Wu S, Wang Y, Sun L, Zhang Z, Jiang Z, Qin Z et al. Decreased expression of dual-specificity phosphatase 9 is associated with poor prognosis in clear cell renal cell carcinoma. BMC Cancer 2011; 11: 413.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Su WP, Tu IH, Hu SW, Yeh HH, Shieh DB, Chen TY et al. HER-2/neu raises SHP-2, stops IFN-gamma anti-proliferation in bladder cancer. Biochem Biophys Res Commun 2007; 356: 181–186.

    Article  CAS  PubMed  Google Scholar 

  118. Kuroda N, Hayashi Y, Matozaki T, Hanioka K, Gotoh A, Wang W et al. Differential expression of SHP2, a protein-tyrosine phosphatase with SRC homology-2 domains, in various types of renal tumour. Virchows Arch 1998; 433: 331–339.

    Article  CAS  PubMed  Google Scholar 

  119. Liu T, Li L, Yang W, Jia H, Xu M, Bi J et al. iASPP is important for bladder cancer cell proliferation. Oncol Res 2011; 19: 125–130.

    Article  CAS  PubMed  Google Scholar 

  120. Bell HS, Ryan KM . iASPP inhibition: increased options in targeting the p53 family for cancer therapy. Cancer Res 2008; 68: 4959–4962.

    Article  CAS  PubMed  Google Scholar 

  121. Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 1997; 275: 1943–1947.

    Article  CAS  PubMed  Google Scholar 

  122. Steck PA, Pershouse MA, Jasser SA, Yung WK, Lin H, Ligon AH et al. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet 1997; 15: 356–362.

    Article  CAS  PubMed  Google Scholar 

  123. Cairns P, Okami K, Halachmi S, Halachmi N, Esteller M, Herman JG et al. Frequent inactivation of PTEN/MMAC1 in primary prostate cancer. Cancer Res 1997; 57: 4997–5000.

    CAS  PubMed  Google Scholar 

  124. Teng DH, Hu R, Lin H, Davis T, Iliev D, Frye C et al. MMAC1/PTEN mutations in primary tumor specimens and tumor cell lines. Cancer Res 1997; 57: 5221–5225.

    CAS  PubMed  Google Scholar 

  125. Whang YE, Wu X, Suzuki H, Reiter RE, Tran C, Vessella RL et al. Inactivation of the tumor suppressor PTEN/MMAC1 in advanced human prostate cancer through loss of expression. Proc Natl Acad Sci USA 1998; 95: 5246–5250.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Vlietstra RJ, van Alewijk DC, Hermans KG, van Steenbrugge GJ, Trapman J . Frequent inactivation of PTEN in prostate cancer cell lines and xenografts. Cancer Res 1998; 58: 2720–2723.

    CAS  PubMed  Google Scholar 

  127. Trotman LC, Niki M, Dotan ZA, Koutcher JA, Di Cristofano A, Xiao A et al. Pten dose dictates cancer progression in the prostate. PLoS Biol 2003; 1: E59.

    Article  PubMed  PubMed Central  Google Scholar 

  128. Chow LM, Baker SJ . PTEN function in normal and neoplastic growth. Cancer Lett 2006; 241: 184–196.

    Article  CAS  PubMed  Google Scholar 

  129. Majumder PK, Febbo PG, Bikoff R, Berger R, Xue Q, McMahon LM et al. mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nat Med 2004; 10: 594–601.

    Article  CAS  PubMed  Google Scholar 

  130. Bayascas JR, Leslie NR, Parsons R, Fleming S, Alessi DR . Hypomorphic mutation of PDK1 suppresses tumorigenesis in PTEN(+/−) mice. Curr Biol 2005; 15: 1839–1846.

    Article  CAS  PubMed  Google Scholar 

  131. Sansal I, Sellers WR . The biology and clinical relevance of the PTEN tumor suppressor pathway. J Clin Oncol 2004; 22: 2954–2963.

    Article  CAS  PubMed  Google Scholar 

  132. Engelman JA . Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer 2009; 9: 550–562.

    Article  CAS  PubMed  Google Scholar 

  133. Murillo H, Huang H, Schmidt LJ, Smith DI, Tindall DJ . Role of PI3K signaling in survival and progression of LNCaP prostate cancer cells to the androgen refractory state. Endocrinology 2001; 142: 4795–4805.

    Article  CAS  PubMed  Google Scholar 

  134. Mulholland DJ, Dedhar S, Wu H, Nelson CC . PTEN and GSK3beta: key regulators of progression to androgen-independent prostate cancer. Oncogene 2006; 25: 329–337.

    Article  CAS  PubMed  Google Scholar 

  135. Wang S, Gao J, Lei Q, Rozengurt N, Pritchard C, Jiao J et al. Prostate-specific deletion of the murine Pten tumor suppressor gene leads to metastatic prostate cancer. Cancer Cell 2003; 4: 209–221.

    Article  CAS  PubMed  Google Scholar 

  136. Li P, Nicosia SV, Bai W . Antagonism between PTEN/MMAC1/TEP-1 and androgen receptor in growth and apoptosis of prostatic cancer cells. J Biol Chem 2001; 276: 20444–20450.

    Article  CAS  PubMed  Google Scholar 

  137. Lin HK, Hu YC, Lee DK, Chang C . Regulation of androgen receptor signaling by PTEN (phosphatase and tensin homolog deleted on chromosome 10) tumor suppressor through distinct mechanisms in prostate cancer cells. Mol Endocrinol 2004; 18: 2409–2423.

    Article  CAS  PubMed  Google Scholar 

  138. Goswami A, Burikhanov R, de Thonel A, Fujita N, Goswami M, Zhao Y et al. Binding and phosphorylation of par-4 by akt is essential for cancer cell survival. Mol Cell 2005; 20: 33–44.

    Article  CAS  PubMed  Google Scholar 

  139. Fernandez-Marcos PJ, Abu-Baker S, Joshi J, Galvez A, Castilla EA, Canamero M et al. Simultaneous inactivation of Par-4 and PTEN in vivo leads to synergistic NF-kappaB activation and invasive prostate carcinoma. Proc Natl Acad Sci USA 2009; 106: 12962–12967.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Cohen PT . Protein phosphatase 1—targeted in many directions. J Cell Sci 2002; 115 (Pt 2): 241–256.

    Article  CAS  PubMed  Google Scholar 

  141. Janssens V, Goris J . Protein phosphatase 2A: a highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling. Biochem J 2001; 353 (Pt 3): 417–439.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Janssens V, Goris J, Van Hoof C . PP2A: the expected tumor suppressor. Curr Opin Genet Dev 2005; 15: 34–41.

    Article  CAS  PubMed  Google Scholar 

  143. Xu Y, Xing Y, Chen Y, Chao Y, Lin Z, Fan E et al. Structure of the protein phosphatase 2A holoenzyme. Cell 2006; 127: 1239–1251.

    Article  CAS  PubMed  Google Scholar 

  144. Singh AP, Bafna S, Chaudhary K, Venkatraman G, Smith L, Eudy JD et al. Genome-wide expression profiling reveals transcriptomic variation and perturbed gene networks in androgen-dependent and androgen-independent prostate cancer cells. Cancer Lett 2008; 259: 28–38.

    Article  CAS  PubMed  Google Scholar 

  145. Cheng Y, Liu W, Kim ST, Sun J, Lu L, Zheng SL et al. Evaluation of PPP2R2A as a prostate cancer susceptibility gene: a comprehensive germline and somatic study. Cancer Genet 2011; 204: 375–381.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Li L, Ren CH, Tahir SA, Ren C, Thompson TC . Caveolin-1 maintains activated Akt in prostate cancer cells through scaffolding domain binding site interactions with and inhibition of serine/threonine protein phosphatases PP1 and PP2A. Mol Cell Biol 2003; 23: 9389–9404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Chen S, Kesler CT, Paschal BM, Balk SP . Androgen receptor phosphorylation and activity are regulated by an association with protein phosphatase 1. J Biol Chem 2009; 284: 25576–25584.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Kim SW, Jung HK, Kim MY . Induction of p27(kip1) by 2,4,3′,5′-tetramethoxystilbene is regulated by protein phosphatase 2A-dependent Akt dephosphorylation in PC-3 prostate cancer cells. Arch Pharm Res 2008; 31: 1187–1194.

    Article  CAS  PubMed  Google Scholar 

  149. Yu N, Kozlowski JM, Park II, Chen L, Zhang Q, Xu D et al. Overexpression of transforming growth factor beta1 in malignant prostate cells is partly caused by a runaway of TGF-beta1 auto-induction mediated through a defective recruitment of protein phosphatase 2A by TGF-beta type I receptor. Urology 2010; 76: 1519 e8–1519 e13.

    Article  Google Scholar 

  150. Bhardwaj A, Singh S, Srivastava SK, Honkanen RE, Reed E, Singh AP . Modulation of protein phosphatase 2A activity alters androgen-independent growth of prostate cancer cells: therapeutic implications. Mol Cancer Ther 2011; 10: 720–731.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Corcoran NM, Najdovska M, Costello AJ . Inorganic selenium retards progression of experimental hormone refractory prostate cancer. J Urol 2004; 171 (2 Pt 1): 907–910.

    Article  CAS  PubMed  Google Scholar 

  152. Corcoran NM, Hovens CM, Michael M, Rosenthal MA, Costello AJ . Open-label, phase I dose-escalation study of sodium selenate, a novel activator of PP2A, in patients with castration-resistant prostate cancer. Br J Cancer 2010; 103: 462–468.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Boutros R, Lobjois V, Ducommun B . CDC25 phosphatases in cancer cells: key players? Good targets? Nat Rev Cancer 2007; 7: 495–507.

    Article  CAS  PubMed  Google Scholar 

  154. Ngan ES, Hashimoto Y, Ma ZQ, Tsai MJ, Tsai SY . Overexpression of Cdc25B, an androgen receptor coactivator, in prostate cancer. Oncogene 2003; 22: 734–739.

    Article  CAS  PubMed  Google Scholar 

  155. Chiu YT, Han HY, Leung SC, Yuen HF, Chau CW, Guo Z et al. CDC25A functions as a novel Ar corepressor in prostate cancer cells. J Mol Biol 2009; 385: 446–456.

    Article  CAS  PubMed  Google Scholar 

  156. Ozen M, Ittmann M . Increased expression and activity of CDC25C phosphatase and an alternatively spliced variant in prostate cancer. Clin Cancer Res 2005; 11: 4701–4706.

    Article  CAS  PubMed  Google Scholar 

  157. Prasad S, Kaur J, Roy P, Kalra N, Shukla Y . Theaflavins induce G2/M arrest by modulating expression of p21waf1/cip1, cdc25C and cyclin B in human prostate carcinoma PC-3 cells. Life Sci 2007; 81: 1323–1331.

    Article  CAS  PubMed  Google Scholar 

  158. Valencia AM, Oliva JL, Bodega G, Chiloeches A, Lopez-Ruiz P, Prieto JC et al. Identification of a protein-tyrosine phosphatase (SHP1) different from that associated with acid phosphatase in rat prostate. FEBS Lett 1997; 406: 42–48.

    Article  CAS  PubMed  Google Scholar 

  159. Zapata PD, Ropero RM, Valencia AM, Buscail L, Lopez JI, Martin-Orozco RM et al. Autocrine regulation of human prostate carcinoma cell proliferation by somatostatin through the modulation of the SH2 domain containing protein tyrosine phosphatase (SHP)-1. J Clin Endocrinol Metab 2002; 87: 915–926.

    Article  CAS  PubMed  Google Scholar 

  160. Cariaga-Martinez AE, Lorenzati MA, Riera MA, Cubilla MA, De La Rossa A, Giorgio EM et al. Tumoral prostate shows different expression pattern of somatostatin receptor 2 (SSTR2) and phosphotyrosine phosphatase SHP-1 (PTPN6) according to tumor progression. Adv Urol 2009; 723831: PubMed PMID: 19365586. Pubmed Central PMCID: 2667939. Epub 2009/04/15. eng.

  161. Tassidis H, Brokken LJ, Jirstrom K, Ehrnstrom R, Ponten F, Ulmert D et al. Immunohistochemical detection of tyrosine phosphatase SHP-1 predicts outcome after radical prostatectomy for localized prostate cancer. Int J Cancer 2010; 126: 2296–2307.

    CAS  PubMed  Google Scholar 

  162. Rodriguez-Ubreva FJ, Cariaga-Martinez AE, Cortes MA, Romero-De Pablos M, Ropero S, Lopez-Ruiz P et al. Knockdown of protein tyrosine phosphatase SHP-1 inhibits G1/S progression in prostate cancer cells through the regulation of components of the cell-cycle machinery. Oncogene 2010; 29: 345–355.

    Article  CAS  PubMed  Google Scholar 

  163. Tassidis H, Brokken LJ, Jirstrom K, Bjartell A, Ulmert D, Harkonen P et al. Low expression of SHP-2 is associated with less favorable prostate cancer outcomes. Tumour Biol 2012, PubMed PMID: 23192641. Epub 2012/11/30. Eng.

  164. Matozaki T, Murata Y, Saito Y, Okazawa H, Ohnishi H . Protein tyrosine phosphatase SHP-2: a proto-oncogene product that promotes Ras activation. Cancer Sci 2009; 100: 1786–1793.

    Article  CAS  PubMed  Google Scholar 

  165. Jemal A, Siegel R, Xu J, Ward E . Cancer statistics, 2010. CA Cancer J Clin 2010; 60: 277–300.

    Article  PubMed  Google Scholar 

  166. Lax SF, Pizer ES, Ronnett BM, Kurman RJ . Comparison of estrogen and progesterone receptor, Ki-67, and p53 immunoreactivity in uterine endometrioid carcinoma and endometrioid carcinoma with squamous, mucinous, secretory, and ciliated cell differentiation. Hum Pathol 1998; 29: 924–931.

    Article  CAS  PubMed  Google Scholar 

  167. Fujimoto T, Nanjyo H, Fukuda J, Nakamura A, Mizunuma H, Yaegashi N et al. Endometrioid uterine cancer: histopathological risk factors of local and distant recurrence. Gynecol Oncol 2009; 112: 342–347.

    Article  PubMed  Google Scholar 

  168. Dellinger TH, Monk BJ . Systemic therapy for recurrent endometrial cancer: a review of North American trials. Expert Rev Anticancer Ther 2009; 9: 905–916.

    Article  PubMed  Google Scholar 

  169. Zhang Q, Claret FX . Phosphatases: the new brakes for cancer development? Enzyme Res 2012; 2012: 659649.

    Article  PubMed  CAS  Google Scholar 

  170. McConechy MK, Anglesio MS, Kalloger SE, Yang W, Senz J, Chow C et al. Subtype-specific mutation of PPP2R1A in endometrial and ovarian carcinomas. J Pathol 2011; 223: 567–573.

    Article  CAS  PubMed  Google Scholar 

  171. Chiappinelli KB, Rimel BJ, Massad LS, Goodfellow PJ . Infrequent methylation of the DUSP6 phosphatase in endometrial cancer. Gynecol Oncol 2010; 119: 146–150.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Gloria-Bottini F, Spina C, Nicotra M, Saccucci P, Ambrosi S, Bottini E . Acid phosphatase locus 1 genetic polymorphism and cancer grading. Am J Med Sci 2012; 344: 32–34.

    Article  PubMed  Google Scholar 

  173. Allard JE, Chandramouli GV, Stagliano K, Hood BL, Litzi T, Shoji Y et al. Analysis of PSPHL as a candidate gene influencing the racial disparity in endometrial cancer. Front Oncol 2012; 2: 65.

    Article  PubMed  PubMed Central  Google Scholar 

  174. Martin-Granados C, Prescott AR, Van Dessel N, Van Eynde A, Arocena M, Klaska IP et al. A role for PP1/NIPP1 in steering migration of human cancer cells. PloS one 2012; 7: e40769.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Zeng Q, Huang Y, Zeng L, Cai D, IPP5 ZhangH . a novel inhibitor of protein phosphatase 1, suppresses tumor growth and progression of cervical carcinoma cells by inducing G2/M arrest. Cancer Genet 2012; 205: 442–452.

    Article  CAS  PubMed  Google Scholar 

  176. Harima Y, Ikeda K, Utsunomiya K, Shiga T, Komemushi A, Kojima H et al. Identification of genes associated with progression and metastasis of advanced cervical cancers after radiotherapy by cDNA microarray analysis. Int J Radiat Oncol Biol Phys 2009; 75: 1232–1239.

    Article  CAS  PubMed  Google Scholar 

  177. He K, He J, Wang S, Yan J . hSHIP induces S-phase arrest and growth inhibition in cervical cancer HeLa cells. J Genet Genomics 2010; 37: 249–255.

    Article  CAS  PubMed  Google Scholar 

  178. Rahmouni S, Cerignoli F, Alonso A, Tsutji T, Henkens R, Zhu C et al. Loss of the VHR dual-specific phosphatase causes cell-cycle arrest and senescence. Nat Cell Biol 2006; 8: 524–531.

    Article  CAS  PubMed  Google Scholar 

  179. Henkens R, Delvenne P, Arafa M, Moutschen M, Zeddou M, Tautz L et al. Cervix carcinoma is associated with an up-regulation and nuclear localization of the dual-specificity protein phosphatase VHR. BMC Cancer 2008; 8: 147.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  180. Wu S, Vossius S, Rahmouni S, Miletic AV, Vang T, Vazquez-Rodriguez J et al. Multidentate small-molecule inhibitors of vaccinia H1-related (VHR) phosphatase decrease proliferation of cervix cancer cells. J Med Chem 2009; 52: 6716–6723.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Huang CC, Wang JM, Kikkawa U, Mukai H, Shen MR, Morita I et al. Calcineurin-mediated dephosphorylation of c-Jun Ser-243 is required for c-Jun protein stability and cell transformation. Oncogene 2008; 27: 2422–2429.

    Article  CAS  PubMed  Google Scholar 

  182. Padma S, Sowjanya AP, Poli UR, Jain M, Rao B, Ramakrishna G . Downregulation of calcineurin activity in cervical carcinoma. Cancer Cell Int 2005; 5: 7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Yeh LS, Hsieh YY, Chang JG, Chang WW, Chang CC, Tsai FJ . Mutation analysis of the tumor suppressor gene PPP2R1B in human cervical cancer. Int J Gynecol Cancer 2007; 17: 868–871.

    Article  PubMed  Google Scholar 

  184. Meng F, Zhao X, Zhang S . SHP-2 phosphatase promotes cervical cancer cell proliferation through inhibiting interferon-beta production. J Obstet Gynaecol Res 2013; 39: 272–279.

    Article  PubMed  CAS  Google Scholar 

  185. Liu J, Wang X, Zhou G, Wang H, Xiang L, Cheng Y et al. Cancerous inhibitor of protein phosphatase 2A is overexpressed in cervical cancer and upregulated by human papillomavirus 16 E7 oncoprotein. Gynecol Oncol 2011; 122: 430–436.

    Article  CAS  PubMed  Google Scholar 

  186. Kurose K, Zhou XP, Araki T, Eng C . Biallelic inactivating mutations and an occult germline mutation of PTEN in primary cervical carcinomas. Genes Chromosomes Cancer 2000; 29: 166–172.

    Article  CAS  PubMed  Google Scholar 

  187. Hsieh SM, Maguire DJ, Lintell NA, McCabe M, Griffiths LR . PTEN and NDUFB8 aberrations in cervical cancer tissue. Adv Exp Med Biol 2007; 599: 31–36.

    Article  CAS  PubMed  Google Scholar 

  188. Kurose K, Zhou XP, Araki T, Cannistra SA, Maher ER, Eng C . Frequent loss of PTEN expression is linked to elevated phosphorylated Akt levels, but not associated with p27 and cyclin D1 expression, in primary epithelial ovarian carcinomas. Am J Pathol 2001; 158: 2097–2106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Lee S, Choi EJ, Jin C, Kim DH . Activation of PI3K/Akt pathway by PTEN reduction and PIK3CA mRNA amplification contributes to cisplatin resistance in an ovarian cancer cell line. Gynecol Oncol 2005; 97: 26–34.

    Article  CAS  PubMed  Google Scholar 

  190. Minaguchi T, Mori T, Kanamori Y, Matsushima M, Yoshikawa H, Taketani Y et al. Growth suppression of human ovarian cancer cells by adenovirus-mediated transfer of the PTEN gene. Cancer Res 1999; 59: 6063–6067.

    CAS  PubMed  Google Scholar 

  191. Takei Y, Saga Y, Mizukami H, Takayama T, Ohwada M, Ozawa K et al. Overexpression of PTEN in ovarian cancer cells suppresses i.p. dissemination and extends survival in mice. Mol Cancer Ther 2008; 7: 704–711.

    Article  CAS  PubMed  Google Scholar 

  192. Wu H, Wang S, Weng D, Xing H, Song X, Zhu T et al. Reversal of the malignant phenotype of ovarian cancer A2780 cells through transfection with wild-type PTEN gene. Cancer Lett 2008; 271: 205–214.

    Article  CAS  PubMed  Google Scholar 

  193. Wu HJ, Hao Q, Wang K, Liu WX, Ma D . [Effects of PTEN gene on invasion and migration of ovarian cancer cell line A2780 and related mechanisms]. Zhonghua Zhong Liu Za Zhi 2011; 33: 165–168.

    CAS  PubMed  Google Scholar 

  194. Wang Y, Sheng Q, Spillman MA, Behbakht K, Gu H . Gab2 regulates the migratory behaviors and E-cadherin expression via activation of the PI3K pathway in ovarian cancer cells. Oncogene 2012; 31: 2512–2520.

    Article  CAS  PubMed  Google Scholar 

  195. Bockelman C, Lassus H, Hemmes A, Leminen A, Westermarck J, Haglund C et al. Prognostic role of CIP2A expression in serous ovarian cancer. Br J Cancer 2011; 105: 989–995.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Sugiyama M, Imai A, Furui T, Tamaya T . Gonadotropin-releasing hormone retards doxorubicin-induced apoptosis and serine/threonine phosphatase inhibition in ovarian cancer cells. Oncol Rep 2005; 13: 813–817.

    CAS  PubMed  Google Scholar 

  197. Imai A, Sugiyama M, Furui T, Tamaya T . Gi protein-mediated translocation of serine/threonine phosphatase to the plasma membrane and apoptosis of ovarian cancer cell in response to gonadotropin-releasing hormone antagonist cetrorelix. J Obstet Gynaecol 2006; 26: 37–41.

    Article  CAS  PubMed  Google Scholar 

  198. Manzano RG, Montuenga LM, Dayton M, Dent P, Kinoshita I, Vicent S et al. CL100 expression is down-regulated in advanced epithelial ovarian cancer and its re-expression decreases its malignant potential. Oncogene 2002; 21: 4435–4447.

    Article  CAS  PubMed  Google Scholar 

  199. Meinhold-Heerlein I, Stenner-Liewen F, Liewen H, Kitada S, Krajewska M, Krajewski S et al. Expression and potential role of Fas-associated phosphatase-1 in ovarian cancer. Am J Pathol 2001; 158: 1335–1344.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Wang B, Zheng WG, Xin XY, Qi RY, Yu YC, Cao YX . [Combinative effects of FAP-1 antisense oligonucleotide and carboplatin on apoptosis of ovarian cancer cell SKOV3]. Ai Zheng 2004; 23: 885–889.

    CAS  PubMed  Google Scholar 

  201. Broggini M, Buraggi G, Brenna A, Riva L, Codegoni AM, Torri V et al. Cell cycle-related phosphatases CDC25A and B expression correlates with survival in ovarian cancer patients. Anticancer Res 2000; 20: 4835–4840.

    CAS  PubMed  Google Scholar 

  202. Mok SC, Kwok TT, Berkowitz RS, Barrett AJ, Tsui FW . Overexpression of the protein tyrosine phosphatase, nonreceptor type 6 (PTPN6), in human epithelial ovarian cancer. Gynecol Oncol 1995; 57: 299–303.

    Article  CAS  PubMed  Google Scholar 

  203. Ali AY, Abedini MR, Tsang BK . The oncogenic phosphatase PPM1D confers cisplatin resistance in ovarian carcinoma cells by attenuating checkpoint kinase 1 and p53 activation. Oncogene 2012; 31: 2175–2186.

    Article  CAS  PubMed  Google Scholar 

  204. Tan DS, Lambros MB, Rayter S, Natrajan R, Vatcheva R, Gao Q et al. PPM1D is a potential therapeutic target in ovarian clear cell carcinomas. Clin Cancer Res 2009; 15: 2269–2280.

    Article  CAS  PubMed  Google Scholar 

  205. Bansal N, Marchion DC, Bicaku E, Xiong Y, Chen N, Stickles XB et al. BCL2 antagonist of cell death kinases, phosphatases, and ovarian cancer sensitivity to cisplatin. J Gynecol Oncol 2012; 23: 35–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Olivero M, Ruggiero T, Saviozzi S, Rasola A, Coltella N, Crispi S et al. Genes regulated by hepatocyte growth factor as targets to sensitize ovarian cancer cells to cisplatin. Mol Cancer Ther 2006; 5: 1126–1135.

    Article  CAS  PubMed  Google Scholar 

  207. Polato F, Codegoni A, Fruscio R, Perego P, Mangioni C, Saha S et al. PRL-3 phosphatase is implicated in ovarian cancer growth. Clin Cancer Res 2005; 11 (19 Pt 1): 6835–6839.

    Article  CAS  PubMed  Google Scholar 

  208. Ren T, Jiang B, Xing X, Dong B, Peng L, Meng L et al. Prognostic significance of phosphatase of regenerating liver-3 expression in ovarian cancer. Pathol Oncol Res 2009; 15: 555–560.

    Article  CAS  PubMed  Google Scholar 

  209. Peng L, Jin G, Wang L, Guo J, Meng L, Shou C . Identification of integrin alpha1 as an interacting protein of protein tyrosine phosphatase PRL-3. Biochem Biophys Res Commun 2006; 342: 179–183.

    Article  CAS  PubMed  Google Scholar 

  210. Guo K, Tang JP, Tan CP, Wang H, Zeng Q . Monoclonal antibodies target intracellular PRL phosphatases to inhibit cancer metastases in mice. Cancer Biol Ther 2008; 7: 750–757.

    Article  CAS  PubMed  Google Scholar 

  211. Tanyi JL, Hasegawa Y, Lapushin R, Morris AJ, Wolf JK, Berchuck A et al. Role of decreased levels of lipid phosphate phosphatase-1 in accumulation of lysophosphatidic acid in ovarian cancer. Clin Cancer Res 2003; 9 (10 Pt 1): 3534–3545.

    CAS  PubMed  Google Scholar 

  212. Omerovic J, Clague MJ, Prior IA . Phosphatome profiling reveals PTPN2, PTPRJ and PTEN as potent negative regulators of PKB/Akt activation in Ras-mutated cancer cells. Biochem J. 2010; 426: 65–72.

    Article  CAS  PubMed  Google Scholar 

  213. Marsit CJ, Zheng S, Aldape K, Hinds PW, Nelson HH, Wiencke JK et al. PTEN expression in non-small-cell lung cancer: evaluating its relation to tumor characteristics, allelic loss, and epigenetic alteration. Hum Pathol 2005; 36: 768–776.

    Article  CAS  PubMed  Google Scholar 

  214. Scrima M, De Marco C, De Vita F, Fabiani F, Franco R, Pirozzi G et al. The nonreceptor-type tyrosine phosphatase PTPN13 is a tumor suppressor gene in non-small cell lung cancer. Am J Pathol 2012; 180: 1202–1214.

    Article  CAS  PubMed  Google Scholar 

  215. Boldrini L, Gisfredi S, Ursino S, Lucchi M, Mussi A, Fontanini G . CDC25B: relationship with angiogenesis and prognosis in non-small cell lung carcinoma. Hum Pathol 2007; 38: 1563–1568.

    Article  CAS  PubMed  Google Scholar 

  216. Moncho-Amor V, Ibanez de Caceres I, Bandres E, Martinez-Poveda B, Orgaz JL, Sanchez-Perez I et al. DUSP1/MKP1 promotes angiogenesis, invasion and metastasis in non-small-cell lung cancer. Oncogene 2011; 30: 668–678.

    Article  CAS  PubMed  Google Scholar 

  217. Chitale D, Gong Y, Taylor BS, Broderick S, Brennan C, Somwar R et al. An integrated genomic analysis of lung cancer reveals loss of DUSP4 in EGFR-mutant tumors. Oncogene 2009; 28: 2773–2783.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Zheng Y, Yang W, Xia Y, Hawke D, Liu DX, Lu Z . Ras-induced and extracellular signal-regulated kinase 1 and 2 phosphorylation-dependent isomerization of protein tyrosine phosphatase (PTP)-PEST by PIN1 promotes FAK dephosphorylation by PTP-PEST. Mol Cell Biol 2011; 31: 4258–4269.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Zhai YF, Beittenmiller H, Wang B, Gould MN, Oakley C, Esselman WJ et al. Increased expression of specific protein tyrosine phosphatases in human breast epithelial cells neoplastically transformed by the neu oncogene. Cancer Res 1993; 53 (10 Suppl): 2272–2278.

    CAS  PubMed  Google Scholar 

  220. Wiener JR, Kerns BJ, Harvey EL, Conaway MR, Iglehart JD, Berchuck A et al. Overexpression of the protein tyrosine phosphatase PTP1B in human breast cancer: association with p185c-erbB-2 protein expression. J Natl Cancer Inst 1994; 86: 372–378.

    Article  CAS  PubMed  Google Scholar 

  221. Bentires-Alj M, Neel BG . Protein-tyrosine phosphatase 1B is required for HER2/Neu-induced breast cancer. Cancer Res 2007; 67: 2420–2424.

    Article  CAS  PubMed  Google Scholar 

  222. Julien SG, Dube N, Read M, Penney J, Paquet M, Han Y et al. Protein tyrosine phosphatase 1B deficiency or inhibition delays ErbB2-induced mammary tumorigenesis and protects from lung metastasis. Nat Genet 2007; 39: 338–346.

    Article  CAS  PubMed  Google Scholar 

  223. Balavenkatraman KK, Aceto N, Britschgi A, Mueller U, Bence KK, Neel BG et al. Epithelial protein-tyrosine phosphatase 1B contributes to the induction of mammary tumors by HER2/Neu but is not essential for tumor maintenance. Mol Cancer Res 2011; 9: 1377–1384.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Glondu-Lassis M, Dromard M, Lacroix-Triki M, Nirde P, Puech C, Knani D et al. PTPL1/PTPN13 regulates breast cancer cell aggressiveness through direct inactivation of Src kinase. Cancer Res 2010; 70: 5116–5126.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Revillion F, Puech C, Rabenoelina F, Chalbos D, Peyrat JP, Freiss G . Expression of the putative tumor suppressor gene PTPN13/PTPL1 is an independent prognostic marker for overall survival in breast cancer. Int J Cancer 2009; 124: 638–643.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. Bompard G, Puech C, Prebois C, Vignon F, Freiss G . Protein-tyrosine phosphatase PTPL1/FAP-1 triggers apoptosis in human breast cancer cells. J Biol Chem 2002; 277: 47861–47869.

    Article  CAS  PubMed  Google Scholar 

  227. Dromard M, Bompard G, Glondu-Lassis M, Puech C, Chalbos D, Freiss G . The putative tumor suppressor gene PTPN13/PTPL1 induces apoptosis through insulin receptor substrate-1 dephosphorylation. Cancer Res 2007; 67: 6806–6813.

    Article  CAS  PubMed  Google Scholar 

  228. Planas-Silva MD, Bruggeman RD, Grenko RT, Stanley Smith J . Role of c-Src and focal adhesion kinase in progression and metastasis of estrogen receptor-positive breast cancer. Biochem Biophys Res Commun 2006; 341: 73–81.

    Article  CAS  PubMed  Google Scholar 

  229. Anbalagan M, Carrier L, Glodowski S, Hangauer D, Shan B, Rowan BG . KX-01, a novel Src kinase inhibitor directed toward the peptide substrate site, synergizes with tamoxifen in estrogen receptor alpha positive breast cancer. Breast Cancer Res Treat 2012; 132: 391–409.

    Article  CAS  PubMed  Google Scholar 

  230. Chen Y, Alvarez EA, Azzam D, Wander SA, Guggisberg N, Jorda M et al. Combined Src and ER blockade impairs human breast cancer proliferation in vitro and in vivo. Breast Cancer Res Treat 2011; 128: 69–78.

    Article  CAS  PubMed  Google Scholar 

  231. Boyault S, Drouet Y, Navarro C, Bachelot T, Lasset C, Treilleux I et al. Mutational characterization of individual breast tumors: TP53 and PI3K pathway genes are frequently and distinctively mutated in different subtypes. Breast Cancer Res Treat 2012; 132: 29–39.

    Article  CAS  PubMed  Google Scholar 

  232. Gonzalez-Angulo AM, Ferrer-Lozano J, Stemke-Hale K, Sahin A, Liu S, Barrera JA et al. PI3K pathway mutations and PTEN levels in primary and metastatic breast cancer. Mol Cancer Ther 2011; 10: 1093–1101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Song MS, Salmena L, Pandolfi PP . The functions and regulation of the PTEN tumour suppressor. Nat Rev Mol Cell Biol 2012; 13: 283–296.

    Article  CAS  PubMed  Google Scholar 

  234. Miller TW, Perez-Torres M, Narasanna A, Guix M, Stal O, Perez-Tenorio G et al. Loss of phosphatase and tensin homologue deleted on chromosome 10 engages ErbB3 and insulin-like growth factor-I receptor signaling to promote antiestrogen resistance in breast cancer. Cancer Res 2009; 69: 4192–4201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  235. Sangai T, Akcakanat A, Chen H, Tarco E, Wu Y, Do KA et al. Biomarkers of response to Akt inhibitor MK-2206 in breast cancer. Clin Cancer Res 2012; 18: 5816–5828.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. Sun T, Aceto N, Meerbrey KL, Kessler JD, Zhou C, Migliaccio I et al. Activation of multiple proto-oncogenic tyrosine kinases in breast cancer via loss of the PTPN12 phosphatase. Cell 2011; 144: 703–718.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. Su F, Ren F, Rong Y, Wang Y, Geng Y, Feng M et al. Protein tyrosine phosphatase Meg2 dephosphorylates signal transducer and activator of transcription 3 and suppresses tumor growth in breast cancer. Breast Cancer Res 2012; 14: R38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  238. Yuan T, Wang Y, Zhao ZJ, Gu H . Protein-tyrosine phosphatase PTPN9 negatively regulates ErbB2 and epidermal growth factor receptor signaling in breast cancer cells. J Biol Chem 2010; 285: 14861–14870.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. Wang HY, Cheng Z, Malbon CC . Overexpression of mitogen-activated protein kinase phosphatases MKP1, MKP2 in human breast cancer. Cancer Lett 2003; 191: 229–237.

    Article  CAS  PubMed  Google Scholar 

  240. Small GW, Shi YY, Higgins LS, Orlowski RZ . Mitogen-activated protein kinase phosphatase-1 is a mediator of breast cancer chemoresistance. Cancer Res 2007; 67: 4459–4466.

    Article  CAS  PubMed  Google Scholar 

  241. Balko JM, Cook RS, Vaught DB, Kuba MG, Miller TW, Bhola NE et al. Profiling of residual breast cancers after neoadjuvant chemotherapy identifies DUSP4 deficiency as a mechanism of drug resistance. Nat Med 2012; 18: 1052–1059.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  242. Nunes-Xavier CE, Tarrega C, Cejudo-Marin R, Frijhoff J, Sandin A, Ostman A et al. Differential up-regulation of MAP kinase phosphatases MKP3/DUSP6 and DUSP5 by Ets2 and c-Jun converge in the control of the growth arrest versus proliferation response of MCF-7 breast cancer cells to phorbol ester. J Biol Chem 2010; 285: 26417–26430.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  243. Tang JP, Tan CP, Li J, Siddique MM, Guo K, Chan SW et al. VHZ is a novel centrosomal phosphatase associated with cell growth and human primary cancers. Mol Cancer 2010; 9: 128.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  244. Bonin S, Brunetti D, Benedetti E, Gorji N, Stanta G . Expression of cyclin-dependent kinases and CDC25a phosphatase is related with recurrences and survival in women with peri- and post-menopausal breast cancer. Virchows Arch 2006; 448: 539–544.

    Article  CAS  PubMed  Google Scholar 

  245. Cangi MG, Cukor B, Soung P, Signoretti S, Moreira G, Ranashinge M et al. Role of the Cdc25A phosphatase in human breast cancer. J Clin Invest 2000; 106: 753–761.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  246. Mehdipour P, Pirouzpanah S, Sarafnejad A, Atri M, Shahrestani ST, Haidari M . Prognostic implication of CDC25A and cyclin E expression on primary breast cancer patients. Cell Biol Int 2009; 33: 1050–1056.

    Article  CAS  PubMed  Google Scholar 

  247. Karagoz ID, Ozaslan M, Cengiz B, Kalender ME, Kilic IH, Oztuzcu S et al. CDC 25A gene 263C/T, -350C/T, and -51C/G polymorphisms in breast carcinoma. Tumour Biol 2010; 31: 597–604.

    Article  CAS  PubMed  Google Scholar 

  248. Feng X, Wu Z, Wu Y, Hankey W, Prior TW, Li L et al. Cdc25A regulates matrix metalloprotease 1 through Foxo1 and mediates metastasis of breast cancer cells. Mol Cell Biol 2011; 31: 3457–3471.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  249. Galaktionov K, Lee AK, Eckstein J, Draetta G, Meckler J, Loda M et al. CDC25 phosphatases as potential human oncogenes. Science 1995; 269: 1575–1577.

    Article  CAS  PubMed  Google Scholar 

  250. Ito Y, Yoshida H, Uruno T, Takamura Y, Miya A, Kuma K et al. Expression of cdc25A and cdc25B phosphatase in breast carcinoma. Breast Cancer 2004; 11: 295–300.

    Article  PubMed  Google Scholar 

  251. Albert H, Battaglia E, Monteiro C, Bagrel D . Genotoxic stress modulates CDC25C phosphatase alternative splicing in human breast cancer cell lines. Mol Oncol 2012; 6: 542–552.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  252. Albert H, Santos S, Battaglia E, Brito M, Monteiro C, Bagrel D . Differential expression of CDC25 phosphatases splice variants in human breast cancer cells. Clin Chem Lab Med 2011; 49: 1707–1714.

    Article  CAS  PubMed  Google Scholar 

  253. Anzick SL, Kononen J, Walker RL, Azorsa DO, Tanner MM, Guan XY et al. AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer. Science 1997; 277: 965–968.

    Article  CAS  PubMed  Google Scholar 

  254. Li C, Liang YY, Feng XH, Tsai SY, Tsai MJ, O’Malley BW . Essential phosphatases and a phospho-degron are critical for regulation of SRC-3/AIB1 coactivator function and turnover. Mol Cell 2008; 31: 835–849.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  255. Wong LL, Zhang D, Chang CF, Koay ES . Silencing of the PP2A catalytic subunit causes HER-2/neu positive breast cancer cells to undergo apoptosis. Exp Cell Res 2010; 316: 3387–3396.

    Article  CAS  PubMed  Google Scholar 

  256. Wong LL, Chang CF, Koay ES, Zhang D . Tyrosine phosphorylation of PP2A is regulated by HER-2 signalling and correlates with breast cancer progression. Int J Oncol 2009; 34: 1291–1301.

    CAS  PubMed  Google Scholar 

  257. Kong W, Jiang X, Mercer WE . Downregulation of Wip-1 phosphatase expression in MCF-7 breast cancer cells enhances doxorubicin-induced apoptosis through p53-mediated transcriptional activation of Bax. Cancer Biol Ther 2009; 8: 555–563.

    Article  CAS  PubMed  Google Scholar 

  258. Pandey RN, Rani R, Yeo EJ, Spencer M, Hu S, Lang RA et al. The Eyes Absent phosphatase-transactivator proteins promote proliferation, transformation, migration, and invasion of tumor cells. Oncogene 2010; 29: 3715–3722.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  259. Farabaugh SM, Micalizzi DS, Jedlicka P, Zhao R, Ford HL . Eya2 is required to mediate the pro-metastatic functions of Six1 via the induction of TGF-beta signaling, epithelial-mesenchymal transition, and cancer stem cell properties. Oncogene 2012; 31: 552–562.

    Article  CAS  PubMed  Google Scholar 

  260. Krueger AB, Dehdashti SJ, Southall N, Marugan JJ, Ferrer M, Li X et al. Identification of a selective small-molecule inhibitor series targeting the Eyes Absent 2 (Eya2) phosphatase activity. J Biomol Screen 2012; 18: 85–96.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  261. Shor AC, Agresta SV, D’Amato GZ, Sondak VK . Therapeutic potential of directed tyrosine kinase inhibitor therapy in sarcomas. Cancer Control 2008; 15: 47–54.

    Article  PubMed  Google Scholar 

  262. Shamay M, Liu J, Li R, Liao G, Shen L, Greenway M et al. A protein array screen for Kaposi’s sarcoma-associated herpesvirus LANA interactors links LANA to TIP60, PP2A activity, and telomere shortening. J Virol 2012; 86: 5179–5191.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  263. Roy D, Dittmer DP . Phosphatase and tensin homolog on chromosome 10 is phosphorylated in primary effusion lymphoma and Kaposi’s sarcoma. Am J Pathol 2011; 179: 2108–2119.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  264. Amant F, de la Rey M, Dorfling CM, van der Walt L, Dreyer G, Dreyer L et al. PTEN mutations in uterine sarcomas. Gynecol Oncol 2002; 85: 165–169.

    Article  CAS  PubMed  Google Scholar 

  265. Grossmann AH, Layfield LJ, Randall RL . Classification, molecular characterization, and the significance of pten alteration in leiomyosarcoma. Sarcoma 2012; 2012: 380896.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  266. Kawaguchi K, Oda Y, Saito T, Takahira T, Yamamoto H, Tamiya S et al. Genetic and epigenetic alterations of the PTEN gene in soft tissue sarcomas. Hum Pathol 2005; 36: 357–363.

    Article  CAS  PubMed  Google Scholar 

  267. Bakken T, He M, Cannon ML . The phosphatase Shp2 is required for signaling by the Kaposi’s sarcoma-associated herpesvirus viral GPCR in primary endothelial cells. Virology 2010; 397: 379–388.

    Article  CAS  PubMed  Google Scholar 

  268. Philpott N, Bakken T, Pennell C, Chen L, Wu J, Cannon M . The Kaposi’s sarcoma-associated herpesvirus G protein-coupled receptor contains an immunoreceptor tyrosine-based inhibitory motif that activates Shp2. J Virol 2011; 85: 1140–1144.

    Article  CAS  PubMed  Google Scholar 

  269. Abaan OD, Levenson A, Khan O, Furth PA, Uren A, Toretsky JA . PTPL1 is a direct transcriptional target of EWS-FLI1 and modulates Ewing’s sarcoma tumorigenesis. Oncogene 2005; 24: 2715–2722.

    Article  CAS  PubMed  Google Scholar 

  270. Siligan C, Ban J, Bachmaier R, Spahn L, Kreppel M, Schaefer KL et al. EWS-FLI1 target genes recovered from Ewing’s sarcoma chromatin. Oncogene 2005; 24: 2512–2524.

    Article  CAS  PubMed  Google Scholar 

  271. Wang J, Chen X, Liu B, Zhu Z . Suppression of PTP1B in gastric cancer cells in vitro induces a change in the genome-wide expression profile and inhibits gastric cancer cell growth. Cell Biol Int 2010; 34: 747–753.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Aleksandra Filipovic for helping in editing the manuscript. JS and GG are supported by grants from the National Institutes of Health Research, Imperial Biomedical Research Centre and Experimental Cancer Medicine Centre, Breast Cancer Campaign, Cancer Research UK and Action Against Cancer.

Author information

Author notes

  1. J Stebbing and L C Lit: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Cancer, Department of Surgery and Cancer, Imperial College London, London, UK

    J Stebbing, L C Lit, H Zhang, R S Darrington, O Melaiu, B Rudraraju & G Giamas

Authors
  1. J Stebbing
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. L C Lit
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. H Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R S Darrington
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. O Melaiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. B Rudraraju
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. G Giamas
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to G Giamas.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Stebbing, J., Lit, L., Zhang, H. et al. The regulatory roles of phosphatases in cancer. Oncogene 33, 939–953 (2014). https://doi.org/10.1038/onc.2013.80

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2013.80

Keywords

This article is cited by

Search

Advanced search

Quick links