Advertisement

Protein tyrosine phosphatases: promising targets in pancreatic ductal adenocarcinoma

  • Mariana Tannús Ruckert
  • Pamela Viani de Andrade
  • Verena Silva Santos
  • Vanessa Silva SilveiraEmail author
Review

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer. It is the fourth leading cause of cancer-related death and is associated with a very poor prognosis. KRAS driver mutations occur in approximately 95% of PDAC cases and cause the activation of several signaling pathways such as mitogen-activated protein kinase (MAPK) pathways. Regulation of these signaling pathways is orchestrated by feedback loops mediated by the balance between protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs), leading to activation or inhibition of its downstream targets. The human PTPome comprises 125 members, and these proteins are classified into three distinct families according to their structure. Since PTP activity description, it has become clear that they have both inhibitory and stimulatory effects on cancer-associated signaling processes and that deregulation of PTP function is closely associated with tumorigenesis. Several PTPs have displayed either tumor suppressor or oncogenic characteristics during the development and progression of PDAC. In this sense, PTPs have been presented as promising candidates for the treatment of human pancreatic cancer, and many PTP inhibitors have been developed since these proteins were first associated with cancer. Nevertheless, some challenges persist regarding the development of effective and safe methods to target these molecules and deliver these drugs. In this review, we discuss the role of PTPs in tumorigenesis as tumor suppressor and oncogenic proteins. We have focused on the differential expression of these proteins in PDAC, as well as their clinical implications and possible targeting for pharmacological inhibition in cancer therapy.

Keywords

Pancreatic cancer Tyrosine phosphatases Dual-specificity phosphatases Molecular targets 

Notes

Acknowledgements

This work was supported by the Fundação de Amparo a Pesquisa do Estado de São Paulo—FAPESP. Research grant no. 2015/10694-5.

References

  1. 1.
    Hidalgo M (2012) New insights into pancreatic cancer biology. Ann Oncol 23(Suppl 10):x135–x138CrossRefPubMedGoogle Scholar
  2. 2.
    Rahib L et al (2014) Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res 74(11):2913–2921CrossRefGoogle Scholar
  3. 3.
    Distler M et al (2013) Evaluation of survival in patients after pancreatic head resection for ductal adenocarcinoma. BMC Surg 13:12CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Kleeff J et al (2016) Pancreatic cancer. Nat Rev Dis Primers 2:16022CrossRefGoogle Scholar
  5. 5.
    Zuckerman DS, Ryan DP (2008) Adjuvant therapy for pancreatic cancer: a review. Cancer 112(2):243–249CrossRefPubMedGoogle Scholar
  6. 6.
    Neesse A et al (2015) Stromal biology and therapy in pancreatic cancer: a changing paradigm. Gut 64(9):1476–1484CrossRefPubMedGoogle Scholar
  7. 7.
    Foucher ED et al (2018) Pancreatic ductal adenocarcinoma: a strong imbalance of good and bad immunological cops in the tumor microenvironment. Front Immunol 9:1044CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Cubilla AL, Fitzgerald PJ (1976) Morphological lesions associated with human primary invasive nonendocrine pancreas cancer. Cancer Res 36(7 PT 2):2690–2698PubMedGoogle Scholar
  9. 9.
    Hruban RH et al (2001) Pancreatic intraepithelial neoplasia: a new nomenclature and classification system for pancreatic duct lesions. Am J Surg Pathol 25(5):579–586CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Macgregor-Das AM, Iacobuzio-Donahue CA (2013) Molecular pathways in pancreatic carcinogenesis. J Surg Oncol 107(1):8–14CrossRefPubMedGoogle Scholar
  11. 11.
    Heinmöller E et al (2000) Molecular analysis of microdissected tumors and preneoplastic intraductal lesions in pancreatic carcinoma. Am J Pathol 157(1):83–92CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Wood LD, Hruban RH (2012) Pathology and molecular genetics of pancreatic neoplasms. Cancer J 18(6):492–501CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Gysin S et al (2011) Therapeutic strategies for targeting ras proteins. Genes Cancer 2(3):359–372CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Jones S et al (2008) Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 321(5897):1801–1806CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Scheffzek K et al (1997) The Ras-RasGAP complex: structural basis for GTPase activation and its loss in oncogenic Ras mutants. Science 277(5324):333–338CrossRefPubMedGoogle Scholar
  16. 16.
    Wagner EF, Nebreda AR (2009) Signal integration by JNK and p38 MAPK pathways in cancer development. Nat Rev Cancer 9(8):537–549CrossRefPubMedGoogle Scholar
  17. 17.
    Bermudez O, Pagès G, Gimond C (2010) The dual-specificity MAP kinase phosphatases: critical roles in development and cancer. Am J Physiol Cell Physiol 299(2):C189–C202CrossRefPubMedGoogle Scholar
  18. 18.
    Hunter T (2014) The genesis of tyrosine phosphorylation. Cold Spring Harb Perspect Biol 6(5):a020644CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Hunter T (2009) Tyrosine phosphorylation: thirty years and counting. Curr Opin Cell Biol 21(2):140–146CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Labbé DP, Hardy S, Tremblay ML (2012) Protein tyrosine phosphatases in cancer: friends and foes! Prog Mol Biol Transl Sci 106:253–306CrossRefPubMedGoogle Scholar
  21. 21.
    Alonso A, Pulido R (2016) The extended human PTPome: a growing tyrosine phosphatase family. FEBS J 283(8):1404–1429CrossRefPubMedGoogle Scholar
  22. 22.
    Andersen JN et al (2004) A genomic perspective on protein tyrosine phosphatases: gene structure, pseudogenes, and genetic disease linkage. FASEB J 18(1):8–30CrossRefPubMedGoogle Scholar
  23. 23.
    Zhang ZY, Wang Y, Dixon JE (1994) Dissecting the catalytic mechanism of protein-tyrosine phosphatases. Proc Natl Acad Sci USA 91(5):1624–1627CrossRefPubMedGoogle Scholar
  24. 24.
    Denu JM et al (1996) Form and function in protein dephosphorylation. Cell 87(3):361–364CrossRefPubMedGoogle Scholar
  25. 25.
    Alonso A et al (2016) The extended family of protein tyrosine phosphatases. Methods Mol Biol 1447:1–23CrossRefPubMedGoogle Scholar
  26. 26.
    Tautz L, Critton DA, Grotegut S (2013) Protein tyrosine phosphatases: structure, function, and implication in human disease. Methods Mol Biol 1053:179–221CrossRefPubMedGoogle Scholar
  27. 27.
    Alonso A et al (2004) Protein tyrosine phosphatases in the human genome. Cell 117(6):699–711CrossRefPubMedGoogle Scholar
  28. 28.
    Andersen JN et al (2001) Structural and evolutionary relationships among protein tyrosine phosphatase domains. Mol Cell Biol 21(21):7117–7136CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Tonks NK, Neel BG (1996) From form to function: signaling by protein tyrosine phosphatases. Cell 87(3):365–368CrossRefPubMedGoogle Scholar
  30. 30.
    Guan KL, Broyles SS, Dixon JE (1991) A Tyr/Ser protein phosphatase encoded by vaccinia virus. Nature 350(6316):359–362CrossRefPubMedGoogle Scholar
  31. 31.
    Nunes-Xavier C et al (2011) Dual-specificity MAP kinase phosphatases as targets of cancer treatment. Anticancer Agents Med Chem 11(1):109–132CrossRefPubMedGoogle Scholar
  32. 32.
    Caunt CJ, Keyse SM (2013) Dual-specificity MAP kinase phosphatases (MKPs): shaping the outcome of MAP kinase signalling. FEBS J 280(2):489–504CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Mester J, Eng C (2013) When overgrowth bumps into cancer: the PTEN-opathies. Am J Med Genet C Semin Med Genet 163C(2):114–121CrossRefPubMedGoogle Scholar
  34. 34.
    Lee YR, Chen M, Pandolfi PP (2018) The functions and regulation of the PTEN tumour suppressor: new modes and prospects. Nat Rev Mol Cell Biol 19(9):547–562CrossRefPubMedGoogle Scholar
  35. 35.
    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):13375–13378CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Blanco-Aparicio C et al (2007) PTEN, more than the AKT pathway. Carcinogenesis 28(7):1379–1386CrossRefPubMedGoogle Scholar
  37. 37.
    Manford A et al (2010) Crystal structure of the yeast Sac1: implications for its phosphoinositide phosphatase function. EMBO J 29(9):1489–1498CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Huang SM et al (2009) Negative regulators of insulin signaling revealed in a genome-wide functional screen. PLoS One 4(9):e6871CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Norris FA, Atkins RC, Majerus PW (1997) The cDNA cloning and characterization of inositol polyphosphate 4-phosphatase type II. Evidence for conserved alternative splicing in the 4-phosphatase family. J Biol Chem 272(38):23859–23864CrossRefPubMedGoogle Scholar
  40. 40.
    Ungewickell A et al (2005) The identification and characterization of two phosphatidylinositol-4,5-bisphosphate 4-phosphatases. Proc Natl Acad Sci USA 102(52):18854–18859CrossRefPubMedGoogle Scholar
  41. 41.
    Sasaki T et al (2009) Mammalian phosphoinositide kinases and phosphatases. Prog Lipid Res 48(6):307–343CrossRefPubMedGoogle Scholar
  42. 42.
    Ivetac I et al (2005) The type Ialpha inositol polyphosphate 4-phosphatase generates and terminates phosphoinositide 3-kinase signals on endosomes and the plasma membrane. Mol Biol Cell 16(5):2218–2233CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Zou J et al (2007) Type I phosphatidylinositol-4,5-bisphosphate 4-phosphatase regulates stress-induced apoptosis. Proc Natl Acad Sci USA 104(43):16834–16839CrossRefPubMedGoogle Scholar
  44. 44.
    Xiang K, Manley JL, Tong L (2012) An unexpected binding mode for a Pol II CTD peptide phosphorylated at Ser7 in the active site of the CTD phosphatase Ssu72. Genes Dev 26(20):2265–2270CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Krishnamurthy S et al (2004) Ssu72 Is an RNA polymerase II CTD phosphatase. Mol Cell 14(3):387–394CrossRefPubMedGoogle Scholar
  46. 46.
    Alho I et al (2013) The role of low-molecular-weight protein tyrosine phosphatase (LMW-PTP ACP1) in oncogenesis. Tumour Biol 34(4):1979–1989CrossRefPubMedGoogle Scholar
  47. 47.
    Souza AC et al (2009) From immune response to cancer: a spot on the low molecular weight protein tyrosine phosphatase. Cell Mol Life Sci 66(7):1140–1153CrossRefPubMedGoogle Scholar
  48. 48.
    Honda R et al (1993) Dephosphorylation of human p34cdc2 kinase on both Thr-14 and Tyr-15 by human cdc25B phosphatase. FEBS Lett 318(3):331–334CrossRefPubMedGoogle Scholar
  49. 49.
    Rudolph J (2002) Catalytic mechanism of Cdc25. Biochemistry 41(49):14613–14623CrossRefPubMedGoogle Scholar
  50. 50.
    Arantes GM (2008) The catalytic acid in the dephosphorylation of the Cdk2-pTpY/CycA protein complex by Cdc25B phosphatase. J Phys Chem B 112(47):15244–15247CrossRefPubMedGoogle Scholar
  51. 51.
    Bollu LR et al (2017) Molecular pathways: targeting protein tyrosine phosphatases in cancer. Clin Cancer Res 23(9):2136–2142CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Motiwala T, Jacob ST (2006) Role of protein tyrosine phosphatases in cancer. Prog Nucleic Acid Res Mol Biol 81:297–329CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Julien SG et al (2011) Inside the human cancer tyrosine phosphatome. Nat Rev Cancer 11(1):35–49CrossRefPubMedGoogle Scholar
  54. 54.
    Wang Z et al (2004) Mutational analysis of the tyrosine phosphatome in colorectal cancers. Science 304(5674):1164–1166CrossRefPubMedGoogle Scholar
  55. 55.
    Korff S et al (2008) Frameshift mutations in coding repeats of protein tyrosine phosphatase genes in colorectal tumors with microsatellite instability. BMC Cancer 8:329CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Xu Y et al (2005) Receptor-type protein-tyrosine phosphatase-kappa regulates epidermal growth factor receptor function. J Biol Chem 280(52):42694–42700CrossRefPubMedGoogle Scholar
  57. 57.
    Lucci MA et al (2010) Expression profile of tyrosine phosphatases in HER2 breast cancer cells and tumors. Cell Oncol 32(5–6):361–372PubMedPubMedCentralGoogle Scholar
  58. 58.
    Shimozato O et al (2015) Receptor-type protein tyrosine phosphatase κ directly dephosphorylates CD133 and regulates downstream AKT activation. Oncogene 34(15):1949–1960CrossRefPubMedGoogle Scholar
  59. 59.
    Veeriah S et al (2009) 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 106(23):9435–9440CrossRefPubMedGoogle Scholar
  60. 60.
    Solomon DA et al (2008) Mutational inactivation of PTPRD in glioblastoma multiforme and malignant melanoma. Cancer Res 68(24):10300–10306CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Hsu HC et al (2018) PTPRT and PTPRD deleterious mutations and deletion predict bevacizumab resistance in metastatic colorectal cancer patients. Cancers (Basel).  https://doi.org/10.3390/cancers10090314 CrossRefGoogle Scholar
  62. 62.
    van Doorn R et al (2005) Epigenetic profiling of cutaneous T-cell lymphoma: promoter hypermethylation of multiple tumor suppressor genes including BCL7a, PTPRG, and p73. J Clin Oncol 23(17):3886–3896CrossRefPubMedGoogle Scholar
  63. 63.
    Wang JF, Dai DQ (2007) Metastatic suppressor genes inactivated by aberrant methylation in gastric cancer. World J Gastroenterol 13(43):5692–5698CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Yeh SH et al (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):1097–1108CrossRefPubMedGoogle Scholar
  65. 65.
    Jacob ST, Motiwala T (2005) Epigenetic regulation of protein tyrosine phosphatases: potential molecular targets for cancer therapy. Cancer Gene Ther 12(8):665–672CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Motiwala T et al (2004) Protein tyrosine phosphatase receptor-type O (PTPRO) exhibits characteristics of a candidate tumor suppressor in human lung cancer. Proc Natl Acad Sci USA 101(38):13844–13849CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Stevenson WS et al (2014) DNA methylation of membrane-bound tyrosine phosphatase genes in acute lymphoblastic leukaemia. Leukemia 28(4):787–793CrossRefPubMedGoogle Scholar
  68. 68.
    Oka T et al (2002) Gene silencing of the tyrosine phosphatase SHP1 gene by aberrant methylation in leukemias/lymphomas. Cancer Res 62(22):6390–6394PubMedGoogle Scholar
  69. 69.
    Khoury JD et al (2004) Methylation of SHP1 gene and loss of SHP1 protein expression are frequent in systemic anaplastic large cell lymphoma. Blood 104(5):1580–1581CrossRefPubMedGoogle Scholar
  70. 70.
    Zhang Q et al (2005) STAT3- and DNA methyltransferase 1-mediated epigenetic silencing of SHP-1 tyrosine phosphatase tumor suppressor gene in malignant T lymphocytes. Proc Natl Acad Sci USA 102(19):6948–6953CrossRefPubMedGoogle Scholar
  71. 71.
    King D, Yeomanson D, Bryant HE (2015) PI3King the lock: targeting the PI3K/Akt/mTOR pathway as a novel therapeutic strategy in neuroblastoma. J Pediatr Hematol Oncol 37(4):245–251CrossRefPubMedGoogle Scholar
  72. 72.
    Asano T et al (2004) The PI 3-kinase/Akt signaling pathway is activated due to aberrant Pten expression and targets transcription factors NF-kappaB and c-Myc in pancreatic cancer cells. Oncogene 23(53):8571–8580CrossRefGoogle Scholar
  73. 73.
    Kinross KM et al (2012) An activating Pik3ca mutation coupled with Pten loss is sufficient to initiate ovarian tumorigenesis in mice. J Clin Invest 122(2):553–557CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    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):289–301CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Song MS, Salmena L, Pandolfi PP (2012) The functions and regulation of the PTEN tumour suppressor. Nat Rev Mol Cell Biol 13(5):283–296CrossRefGoogle Scholar
  76. 76.
    Yin Y et al (2003) PAC1 phosphatase is a transcription target of p53 in signalling apoptosis and growth suppression. Nature 422(6931):527–531CrossRefPubMedGoogle Scholar
  77. 77.
    Lin SC et al (2011) Suppression of dual-specificity phosphatase-2 by hypoxia increases chemoresistance and malignancy in human cancer cells. J Clin Invest 121(5):1905–1916CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Zhang Z et al (2010) Dual specificity phosphatase 6 (DUSP6) is an ETS-regulated negative feedback mediator of oncogenic ERK signaling in lung cancer cells. Carcinogenesis 31(4):577–586CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Furukawa T et al (2003) Potential tumor suppressive pathway involving DUSP6/MKP-3 in pancreatic cancer. Am J Pathol 162(6):1807–1815CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Chan DW et al (2008) Loss of MKP3 mediated by oxidative stress enhances tumorigenicity and chemoresistance of ovarian cancer cells. Carcinogenesis 29(9):1742–1750CrossRefPubMedGoogle Scholar
  81. 81.
    Wong VC et al (2012) Tumor suppressor dual-specificity phosphatase 6 (DUSP6) impairs cell invasion and epithelial-mesenchymal transition (EMT)-associated phenotype. Int J Cancer 130(1):83–95CrossRefPubMedGoogle Scholar
  82. 82.
    Messina S et al (2011) Dual-specificity phosphatase DUSP6 has tumor-promoting properties in human glioblastomas. Oncogene 30(35):3813–3820CrossRefPubMedGoogle Scholar
  83. 83.
    Song H et al (2015) Silencing of DUSP6 gene by RNAi-mediation inhibits proliferation and growth in MDA-MB-231 breast cancer cells: an in vitro study. Int J Clin Exp Med 8(7):10481–10490PubMedPubMedCentralGoogle Scholar
  84. 84.
    Ekerot M et al (2008) Negative-feedback regulation of FGF signalling by DUSP6/MKP-3 is driven by ERK1/2 and mediated by Ets factor binding to a conserved site within the DUSP6/MKP-3 gene promoter. Biochem J 412(2):287–298CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Znosko WA et al (2010) Overlapping functions of Pea3 ETS transcription factors in FGF signaling during zebrafish development. Dev Biol 342(1):11–25CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Li W et al (2012) Increased levels of DUSP6 phosphatase stimulate tumourigenesis in a molecularly distinct melanoma subtype. Pigment Cell Melanoma Res 25(2):188–199CrossRefPubMedGoogle Scholar
  87. 87.
    Muda M et al (1997) Molecular cloning and functional characterization of a novel mitogen-activated protein kinase phosphatase, MKP-4. J Biol Chem 272(8):5141–5151CrossRefPubMedGoogle Scholar
  88. 88.
    Dickinson RJ et al (2002) Characterization of a murine gene encoding a developmentally regulated cytoplasmic dual-specificity mitogen-activated protein kinase phosphatase. Biochem J 364(Pt 1):145–155CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Liu Y et al (2007) Microtubule disruption and tumor suppression by mitogen-activated protein kinase phosphatase 4. Cancer Res 67(22):10711–10719CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Wu F et al (2015) Epigenetic silencing of DUSP9 induces the proliferation of human gastric cancer by activating JNK signaling. Oncol Rep 34(1):121–128CrossRefPubMedGoogle Scholar
  91. 91.
    Huang J et al (2011) Activation of Src and transformation by an RPTPα splice mutant found in human tumours. EMBO J 30(15):3200–3211CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Elson A (2018) Stepping out of the shadows: oncogenic and tumor-promoting protein tyrosine phosphatases. Int J Biochem Cell Biol 96:135–147CrossRefPubMedGoogle Scholar
  93. 93.
    Zheng XM, Resnick RJ, Shalloway D (2000) A phosphotyrosine displacement mechanism for activation of Src by PTPalpha. EMBO J 19(5):964–978CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Meyer DS et al (2014) Tyrosine phosphatase PTPα contributes to HER2-evoked breast tumor initiation and maintenance. Oncogene 33(3):398–402CrossRefPubMedGoogle Scholar
  95. 95.
    Zheng X, Resnick RJ, Shalloway D (2008) Apoptosis of estrogen-receptor negative breast cancer and colon cancer cell lines by PTP alpha and src RNAi. Int J Cancer 122(9):1999–2007CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    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):26116–26122CrossRefPubMedGoogle Scholar
  97. 97.
    Berman-Golan D, Elson A (2007) Neu-mediated phosphorylation of protein tyrosine phosphatase epsilon is critical for activation of Src in mammary tumor cells. Oncogene 26(49):7028–7037CrossRefPubMedGoogle Scholar
  98. 98.
    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):15579–15586CrossRefPubMedGoogle Scholar
  99. 99.
    Spring K et al (2015) The protein tyrosine phosphatase DEP-1/PTPRJ promotes breast cancer cell invasion and metastasis. Oncogene 34(44):5536–5547CrossRefPubMedGoogle Scholar
  100. 100.
    Fournier P et al (2016) Tyrosine phosphatase PTPRJ/DEP-1 is an essential promoter of vascular permeability, angiogenesis, and tumor progression. Cancer Res 76(17):5080–5091CrossRefPubMedGoogle Scholar
  101. 101.
    Trapasso F et al (2000) Rat protein tyrosine phosphatase eta suppresses the neoplastic phenotype of retrovirally transformed thyroid cells through the stabilization of p27(Kip1). Mol Cell Biol 20(24):9236–9246CrossRefPubMedPubMedCentralGoogle Scholar
  102. 102.
    Iuliano R et al (2003) An adenovirus carrying the rat protein tyrosine phosphatase eta suppresses the growth of human thyroid carcinoma cell lines in vitro and in vivo. Cancer Res 63(4):882–886PubMedGoogle Scholar
  103. 103.
    Trapasso F et al (2004) Restoration of receptor-type protein tyrosine phosphatase eta function inhibits human pancreatic carcinoma cell growth in vitro and in vivo. Carcinogenesis 25(11):2107–2114CrossRefPubMedGoogle Scholar
  104. 104.
    Ruivenkamp CA et al (2002) Ptprj is a candidate for the mouse colon-cancer susceptibility locus Scc1 and is frequently deleted in human cancers. Nat Genet 31(3):295–300CrossRefPubMedGoogle Scholar
  105. 105.
    Arora D et al (2011) Protein-tyrosine phosphatase DEP-1 controls receptor tyrosine kinase FLT3 signaling. J Biol Chem 286(13):10918–10929CrossRefPubMedPubMedCentralGoogle Scholar
  106. 106.
    Bourgonje AM et al (2014) Intracellular and extracellular domains of protein tyrosine phosphatase PTPRZ-B differentially regulate glioma cell growth and motility. Oncotarget 5(18):8690–8702CrossRefPubMedPubMedCentralGoogle Scholar
  107. 107.
    Müller S et al (2003) A role for receptor tyrosine phosphatase zeta in glioma cell migration. Oncogene 22(43):6661–6668CrossRefPubMedGoogle Scholar
  108. 108.
    Ulbricht U et al (2006) RNA interference targeting protein tyrosine phosphatase zeta/receptor-type protein tyrosine phosphatase beta suppresses glioblastoma growth in vitro and in vivo. J Neurochem 98(5):1497–1506CrossRefPubMedGoogle Scholar
  109. 109.
    Sethi G et al (2015) PTN signaling: components and mechanistic insights in human ovarian cancer. Mol Carcinog 54(12):1772–1785CrossRefPubMedGoogle Scholar
  110. 110.
    Xu R et al (2005) Overexpression of Shp2 tyrosine phosphatase is implicated in leukemogenesis in adult human leukemia. Blood 106(9):3142–3149CrossRefPubMedPubMedCentralGoogle Scholar
  111. 111.
    Zhou X et al (2008) SHP2 is up-regulated in breast cancer cells and in infiltrating ductal carcinoma of the breast, implying its involvement in breast oncogenesis. Histopathology 53(4):389–402CrossRefPubMedGoogle Scholar
  112. 112.
    Matozaki T et al (2009) Protein tyrosine phosphatase SHP-2: a proto-oncogene product that promotes Ras activation. Cancer Sci 100(10):1786–1793CrossRefGoogle Scholar
  113. 113.
    Mohi MG, Neel BG (2007) The role of Shp2 (PTPN11) in cancer. Curr Opin Genet Dev 17(1):23–30CrossRefGoogle Scholar
  114. 114.
    Bard-Chapeau EA et al (2011) Ptpn11/Shp2 acts as a tumor suppressor in hepatocellular carcinogenesis. Cancer Cell 19(5):629–639CrossRefPubMedPubMedCentralGoogle Scholar
  115. 115.
    Bard-Chapeau EA et al (2006) Concerted functions of Gab1 and Shp2 in liver regeneration and hepatoprotection. Mol Cell Biol 26(12):4664–4674CrossRefPubMedPubMedCentralGoogle Scholar
  116. 116.
    Dance M et al (2008) The molecular functions of Shp2 in the Ras/Mitogen-activated protein kinase (ERK1/2) pathway. Cell Signal 20(3):453–459CrossRefPubMedGoogle Scholar
  117. 117.
    Bunda S et al (2015) Inhibition of SHP2-mediated dephosphorylation of Ras suppresses oncogenesis. Nat Commun 6:8859CrossRefPubMedPubMedCentralGoogle Scholar
  118. 118.
    Zhou XD, Agazie YM (2008) Inhibition of SHP2 leads to mesenchymal to epithelial transition in breast cancer cells. Cell Death Differ 15(6):988–996CrossRefPubMedGoogle Scholar
  119. 119.
    Huang Y et al (2018) The roles of protein tyrosine phosphatases in hepatocellular carcinoma. Cancers (Basel).  https://doi.org/10.3390/cancers10030082 CrossRefPubMedPubMedCentralGoogle Scholar
  120. 120.
    Jiang C et al (2012) The tumor suppressor role of Src homology phosphotyrosine phosphatase 2 in hepatocellular carcinoma. J Cancer Res Clin Oncol 138(4):637–646CrossRefPubMedGoogle Scholar
  121. 121.
    Luo X et al (2016) Dual Shp2 and pten deficiencies promote non-alcoholic steatohepatitis and genesis of liver tumor-initiating cells. Cell Rep 17(11):2979–2993CrossRefPubMedPubMedCentralGoogle Scholar
  122. 122.
    Qi C et al (2017) Shp2 inhibits proliferation of esophageal squamous cell cancer via dephosphorylation of Stat3. Int J Mol Sci.  https://doi.org/10.3390/ijms18010134 CrossRefPubMedPubMedCentralGoogle Scholar
  123. 123.
    Bhattacharyya S, Feferman L, Tobacman JK (2017) Chondroitin sulfatases differentially regulate Wnt signaling in prostate stem cells through effects on SHP2, phospho-ERK1/2, and Dickkopf Wnt signaling pathway inhibitor (DKK3). Oncotarget 8(59):100242–100260CrossRefPubMedPubMedCentralGoogle Scholar
  124. 124.
    Lessard L, Stuible M, Tremblay ML (2010) The two faces of PTP1B in cancer. Biochim Biophys Acta 1804(3):613–619CrossRefPubMedGoogle Scholar
  125. 125.
    Wang J et al (2012) PTP1B expression contributes to gastric cancer progression. Med Oncol 29(2):948–956CrossRefPubMedGoogle Scholar
  126. 126.
    Wang N et al (2015) Frequent amplification of PTP1B is associated with poor survival of gastric cancer patients. Cell Cycle 14(5):732–743CrossRefPubMedPubMedCentralGoogle Scholar
  127. 127.
    Julien SG et al (2007) Protein tyrosine phosphatase 1B deficiency or inhibition delays ErbB2-induced mammary tumorigenesis and protects from lung metastasis. Nat Genet 39(3):338–346CrossRefPubMedGoogle Scholar
  128. 128.
    Lessard L et al (2012) PTP1B is an androgen receptor-regulated phosphatase that promotes the progression of prostate cancer. Cancer Res 72(6):1529–1537CrossRefPubMedPubMedCentralGoogle Scholar
  129. 129.
    Hoekstra E et al (2016) Increased PTP1B expression and phosphatase activity in colorectal cancer results in a more invasive phenotype and worse patient outcome. Oncotarget 7(16):21922–21938CrossRefPubMedPubMedCentralGoogle Scholar
  130. 130.
    Magistrelli G, Toma S, Isacchi A (1996) Substitution of two variant residues in the protein tyrosine phosphatase-like PTP35/IA-2 sequence reconstitutes catalytic activity. Biochem Biophys Res Commun 227(2):581–588CrossRefPubMedGoogle Scholar
  131. 131.
    Xu H et 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):278CrossRefPubMedPubMedCentralGoogle Scholar
  132. 132.
    Sorokin AV et al (2015) Aberrant expression of proPTPRN2 in cancer cells confers resistance to apoptosis. Cancer Res 75(9):1846–1858CrossRefPubMedPubMedCentralGoogle Scholar
  133. 133.
    Sengelaub CA et al (2016) PTPRN2 and PLCβ1 promote metastatic breast cancer cell migration through PI(4,5)P2-dependent actin remodeling. EMBO J 35(1):62–76CrossRefPubMedGoogle Scholar
  134. 134.
    Keyse SM (2008) Dual-specificity MAP kinase phosphatases (MKPs) and cancer. Cancer Metastasis Rev 27(2):253–261CrossRefPubMedPubMedCentralGoogle Scholar
  135. 135.
    Loda M et al (1996) Expression of mitogen-activated protein kinase phosphatase-1 in the early phases of human epithelial carcinogenesis. Am J Pathol 149(5):1553–1564PubMedPubMedCentralGoogle Scholar
  136. 136.
    Keyse SM, Emslie EA (1992) Oxidative stress and heat shock induce a human gene encoding a protein-tyrosine phosphatase. Nature 359(6396):644–647CrossRefPubMedGoogle Scholar
  137. 137.
    Laderoute KR et al (1999) Mitogen-activated protein kinase phosphatase-1 (MKP-1) expression is induced by low oxygen conditions found in solid tumor microenvironments. A candidate MKP for the inactivation of hypoxia-inducible stress-activated protein kinase/c-Jun N-terminal protein kinase activity. J Biol Chem 274(18):12890–12897CrossRefPubMedGoogle Scholar
  138. 138.
    Magi-Galluzzi C et al (1998) Mitogen-activated protein kinases and apoptosis in PIN. Virchows Arch 432(5):407–413CrossRefPubMedGoogle Scholar
  139. 139.
    Magi-Galluzzi C et al (1997) Mitogen-activated protein kinase phosphatase 1 is overexpressed in prostate cancers and is inversely related to apoptosis. Lab Invest 76(1):37–51PubMedGoogle Scholar
  140. 140.
    Denkert C et al (2002) Expression of mitogen-activated protein kinase phosphatase-1 (MKP-1) in primary human ovarian carcinoma. Int J Cancer 102(5):507–513CrossRefPubMedGoogle Scholar
  141. 141.
    Vicent S et al (2004) Mitogen-activated protein kinase phosphatase-1 is overexpressed in non-small cell lung cancer and is an independent predictor of outcome in patients. Clin Cancer Res 10(11):3639–3649CrossRefPubMedPubMedCentralGoogle Scholar
  142. 142.
    Lim EH et al (2003) Feasibility of using low-volume tissue samples for gene expression profiling of advanced non-small cell lung cancers. Clin Cancer Res 9(16 Pt 1):5980–5987PubMedGoogle Scholar
  143. 143.
    Chattopadhyay S et al (2006) MKP1/CL100 controls tumor growth and sensitivity to cisplatin in non-small-cell lung cancer. Oncogene 25(23):3335–3345CrossRefPubMedPubMedCentralGoogle Scholar
  144. 144.
    Teng F et al (2018) DUSP1 induces apatinib resistance by activating the MAPK pathway in gastric cancer. Oncol Rep 40(3):1203–1222PubMedPubMedCentralGoogle Scholar
  145. 145.
    Sieben NL et al (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):7257–7264CrossRefGoogle Scholar
  146. 146.
    Givant-Horwitz V et al (2004) The PAC-1 dual specificity phosphatase predicts poor outcome in serous ovarian carcinoma. Gynecol Oncol 93(2):517–523CrossRefPubMedGoogle Scholar
  147. 147.
    Levy-Nissenbaum O et al (2003) Dual-specificity phosphatase Pyst2-L is constitutively highly expressed in myeloid leukemia and other malignant cells. Oncogene 22(48):7649–7660CrossRefPubMedGoogle Scholar
  148. 148.
    den Hollander P et al (2016) Phosphatase PTP4A3 promotes triple-negative breast cancer growth and predicts poor patient survival. Cancer Res 76(7):1942–1953CrossRefGoogle Scholar
  149. 149.
    Fiordalisi JJ et al (2013) Src-mediated phosphorylation of the tyrosine phosphatase PRL-3 is required for PRL-3 promotion of Rho activation, motility and invasion. PLoS One 8(5):e64309CrossRefPubMedPubMedCentralGoogle Scholar
  150. 150.
    Walls CD et al (2013) Phosphatase of regenerating liver 3 (PRL3) provokes a tyrosine phosphoproteome to drive prometastatic signal transduction. Mol Cell Proteom 12(12):3759–3777CrossRefGoogle Scholar
  151. 151.
    Cramer JM et al (2014) Deletion of Ptp4a3 reduces clonogenicity and tumor-initiation ability of colitis-associated cancer cells in mice. Stem Cell Res 13(1):164–171CrossRefPubMedPubMedCentralGoogle Scholar
  152. 152.
    Hardy S, Julien SG, Tremblay ML (2012) Impact of oncogenic protein tyrosine phosphatases in cancer. Anticancer Agents Med Chem 12(1):4–18CrossRefPubMedGoogle Scholar
  153. 153.
    Foehr ED et al (2005) FAS associated phosphatase (FAP-1) blocks apoptosis of astrocytomas through dephosphorylation of FAS. J Neurooncol 74(3):241–248CrossRefPubMedGoogle Scholar
  154. 154.
    Meinhold-Heerlein I et al (2001) Expression and potential role of Fas-associated phosphatase-1 in ovarian cancer. Am J Pathol 158(4):1335–1344CrossRefPubMedPubMedCentralGoogle Scholar
  155. 155.
    Abaan OD et al (2005) PTPL1 is a direct transcriptional target of EWS-FLI1 and modulates Ewing’s Sarcoma tumorigenesis. Oncogene 24(16):2715–2722CrossRefPubMedGoogle Scholar
  156. 156.
    Sun PH et al (2013) Receptor-like protein tyrosine phosphatase κ negatively regulates the apoptosis of prostate cancer cells via the JNK pathway. Int J Oncol 43(5):1560–1568CrossRefPubMedGoogle Scholar
  157. 157.
    Ardini E et al (2000) Expression of protein tyrosine phosphatase alpha (RPTPalpha) in human breast cancer correlates with low tumor grade, and inhibits tumor cell growth in vitro and in vivo. Oncogene 19(43):4979–4987CrossRefPubMedGoogle Scholar
  158. 158.
    Kabir NN, Rönnstrand L, Kazi JU (2013) Deregulation of protein phosphatase expression in acute myeloid leukemia. Med Oncol 30(2):517CrossRefPubMedGoogle Scholar
  159. 159.
    Levea CM et al (2000) PTP LAR expression compared to prognostic indices in metastatic and non-metastatic breast cancer. Breast Cancer Res Treat 64(2):221–228CrossRefPubMedGoogle Scholar
  160. 160.
    Wakim J et al (2017) The PTPROt tyrosine phosphatase functions as an obligate haploinsufficient tumor suppressor in vivo in B-cell chronic lymphocytic leukemia. Oncogene 36(26):3686–3694CrossRefPubMedGoogle Scholar
  161. 161.
    Ulbricht U et al (2003) Expression and function of the receptor protein tyrosine phosphatase zeta and its ligand pleiotrophin in human astrocytomas. J Neuropathol Exp Neurol 62(12):1265–1275CrossRefPubMedGoogle Scholar
  162. 162.
    Seo Y et al (1997) Overexpression of SAP-1, a transmembrane-type protein tyrosine phosphatase, in human colorectal cancers. Biochem Biophys Res Commun 231(3):705–711CrossRefPubMedGoogle Scholar
  163. 163.
    Sato T et al (2015) Prognostic implication of PTPRH hypomethylation in non-small cell lung cancer. Oncol Rep 34(3):1137–1145CrossRefPubMedPubMedCentralGoogle Scholar
  164. 164.
    Kaur H et al (2012) Protein tyrosine phosphatase mu regulates glioblastoma cell growth and survival in vivo. Neuro Oncol 14(5):561–573CrossRefPubMedPubMedCentralGoogle Scholar
  165. 165.
    Phillips-Mason PJ, Craig SE, Brady-Kalnay SM (2014) A protease storm cleaves a cell-cell adhesion molecule in cancer: multiple proteases converge to regulate PTPmu in glioma cells. J Cell Biochem 115(9):1609–1623CrossRefPubMedPubMedCentralGoogle Scholar
  166. 166.
    Burgoyne AM et al (2009) Proteolytic cleavage of protein tyrosine phosphatase mu regulates glioblastoma cell migration. Cancer Res 69(17):6960–6968CrossRefPubMedPubMedCentralGoogle Scholar
  167. 167.
    Liu Y et al (2014) Knockdown of protein tyrosine phosphatase receptor U inhibits growth and motility of gastric cancer cells. Int J Clin Exp Pathol 7(9):5750–5761PubMedPubMedCentralGoogle Scholar
  168. 168.
    Zhu Z et al (2014) Protein tyrosine phosphatase receptor U (PTPRU) is required for glioma growth and motility. Carcinogenesis 35(8):1901–1910CrossRefPubMedGoogle Scholar
  169. 169.
    Kumar V et al (2016) CD45 phosphatase inhibits STAT3 transcription factor activity in myeloid cells and promotes tumor-associated macrophage differentiation. Immunity 44(2):303–315CrossRefPubMedPubMedCentralGoogle Scholar
  170. 170.
    Teng HW et al (2016) Protein tyrosine phosphatase 1B targets PITX1/p120RasGAP thus showing therapeutic potential in colorectal carcinoma. Sci Rep 6:35308CrossRefPubMedPubMedCentralGoogle Scholar
  171. 171.
    Tai WT et al (2016) Protein tyrosine phosphatase 1B dephosphorylates PITX1 and regulates p120RasGAP in hepatocellular carcinoma. Hepatology 63(5):1528–1543CrossRefPubMedGoogle Scholar
  172. 172.
    Liu H et al (2015) PTP1B promotes cell proliferation and metastasis through activating src and ERK1/2 in non-small cell lung cancer. Cancer Lett 359(2):218–225CrossRefPubMedGoogle Scholar
  173. 173.
    Mei W et al (2016) Cell transformation by PTP1B truncated mutants found in human colon and thyroid tumors. PLoS One 11(11):e0166538CrossRefPubMedPubMedCentralGoogle Scholar
  174. 174.
    Zahn M et al (2017) A novel PTPN1 splice variant upregulates JAK/STAT activity in classical Hodgkin lymphoma cells. Blood 129(11):1480–1490CrossRefPubMedGoogle Scholar
  175. 175.
    LaMontagne KR et al (1998) Protein tyrosine phosphatase 1B antagonizes signalling by oncoprotein tyrosine kinase p210 bcr-abl in vivo. Mol Cell Biol 18(5):2965–2975CrossRefPubMedPubMedCentralGoogle Scholar
  176. 176.
    Alvira D et al (2011) Inhibition of protein-tyrosine phosphatase 1B (PTP1B) mediates ubiquitination and degradation of Bcr-Abl protein. J Biol Chem 286(37):32313–32323CrossRefPubMedPubMedCentralGoogle Scholar
  177. 177.
    Bentires-Alj M, Neel BG (2007) Protein-tyrosine phosphatase 1B is required for HER2/Neu-induced breast cancer. Cancer Res 67(6):2420–2424CrossRefPubMedGoogle Scholar
  178. 178.
    Kleppe M et al (2010) Deletion of the protein tyrosine phosphatase gene PTPN2 in T-cell acute lymphoblastic leukemia. Nat Genet 42(6):530–535CrossRefPubMedPubMedCentralGoogle Scholar
  179. 179.
    Young RM, Polsky A, Refaeli Y (2009) TC-PTP is required for the maintenance of MYC-driven B-cell lymphomas. Blood 114(24):5016–5023CrossRefPubMedPubMedCentralGoogle Scholar
  180. 180.
    Hou SW et al (2010) PTPH1 dephosphorylates and cooperates with p38gamma MAPK to increase ras oncogenesis through PDZ-mediated interaction. Cancer Res 70(7):2901–2910CrossRefPubMedPubMedCentralGoogle Scholar
  181. 181.
    Zhi HY et al (2011) PTPH1 cooperates with vitamin D receptor to stimulate breast cancer growth through their mutual stabilization. Oncogene 30(14):1706–1715CrossRefPubMedGoogle Scholar
  182. 182.
    Gao Q et al (2014) Activating mutations in PTPN3 promote cholangiocarcinoma cell proliferation and migration and are associated with tumor recurrence in patients. Gastroenterology 146(5):1397–1407CrossRefPubMedGoogle Scholar
  183. 183.
    Shi ZH et al (2016) PTPH1 promotes tumor growth and metastasis in human glioma. Eur Rev Med Pharmacol Sci 20(18):3777–3787PubMedGoogle Scholar
  184. 184.
    Zheng J et al (2016) Expression and prognosis value of SHP2 in patients with pancreatic ductal adenocarcinoma. Tumour Biol 37(6):7853–7859CrossRefPubMedGoogle Scholar
  185. 185.
    Gomes EG, Connelly SF, Summy JM (2013) Targeting the yin and the yang: combined inhibition of the tyrosine kinase c-Src and the tyrosine phosphatase SHP-2 disrupts pancreatic cancer signaling and biology in vitro and tumor formation in vivo. Pancreas 42(5):795–806CrossRefPubMedGoogle Scholar
  186. 186.
    Grosskopf S et al (2015) Selective inhibitors of the protein tyrosine phosphatase SHP2 block cellular motility and growth of cancer cells in vitro and in vivo. ChemMedChem 10(5):815–826CrossRefPubMedGoogle Scholar
  187. 187.
    Mello SS et al (2017) A p53 super-tumor suppressor reveals a tumor suppressive p53-Ptpn14-Yap axis in pancreatic cancer. Cancer Cell 32(4):460–473.e6CrossRefPubMedPubMedCentralGoogle Scholar
  188. 188.
    Carlucci A et al (2010) PTPD1 supports receptor stability and mitogenic signaling in bladder cancer cells. J Biol Chem 285(50):39260–39270CrossRefPubMedPubMedCentralGoogle Scholar
  189. 189.
    Wu ZZ, Lu HP, Chao CC (2010) Identification and functional analysis of genes which confer resistance to cisplatin in tumor cells. Biochem Pharmacol 80(2):262–276CrossRefPubMedGoogle Scholar
  190. 190.
    Foo WC et al (2013) Loss of phosphatase and tensin homolog expression is associated with recurrence and poor prognosis in patients with pancreatic ductal adenocarcinoma. Hum Pathol 44(6):1024–1030CrossRefPubMedGoogle Scholar
  191. 191.
    Liao Q et al (2003) Down-regulation of the dual-specificity phosphatase MKP-1 suppresses tumorigenicity of pancreatic cancer cells. Gastroenterology 124(7):1830–1845CrossRefPubMedGoogle Scholar
  192. 192.
    Hijiya N et al (2016) Genomic loss of DUSP4 contributes to the progression of intraepithelial neoplasm of pancreas to invasive carcinoma. Cancer Res 76(9):2612–2625CrossRefPubMedGoogle Scholar
  193. 193.
    Lee J et al (2016) DUSP28 links regulation of Mucin 5B and Mucin 16 to migration and survival of AsPC-1 human pancreatic cancer cells. Tumour Biol 37(9):12193–12202CrossRefPubMedGoogle Scholar
  194. 194.
    Lee J et al (2017) Autocrine DUSP28 signaling mediates pancreatic cancer malignancy via regulation of PDGF-A. Sci Rep 7(1):12760CrossRefPubMedPubMedCentralGoogle Scholar
  195. 195.
    Wang D et al (2014) DUSP28 contributes to human hepatocellular carcinoma via regulation of the p38 MAPK signaling. Int J Oncol 45(6):2596–2604CrossRefPubMedGoogle Scholar
  196. 196.
    Stephens B et al (2008) Small interfering RNA-mediated knockdown of PRL phosphatases results in altered Akt phosphorylation and reduced clonogenicity of pancreatic cancer cells. Mol Cancer Ther 7(1):202–210CrossRefPubMedGoogle Scholar
  197. 197.
    Ruess DA et al (2018) Mutant KRAS-driven cancers depend on PTPN11/SHP2 phosphatase. Nat Med 24(7):954–960CrossRefPubMedGoogle Scholar
  198. 198.
    Fedele C et al. (2018) SHP2 inhibition prevents adaptive resistance to mek inhibitors in multiple cancer models. Cancer Discov 8(10):1237–1249CrossRefPubMedGoogle Scholar
  199. 199.
    Krishna M, Narang H (2008) The complexity of mitogen-activated protein kinases (MAPKs) made simple. Cell Mol Life Sci 65(22):3525–3544CrossRefPubMedGoogle Scholar
  200. 200.
    Bang YJ et al (1998) Increased MAPK activity and MKP-1 overexpression in human gastric adenocarcinoma. Biochem Biophys Res Commun 250(1):43–47CrossRefPubMedGoogle Scholar
  201. 201.
    Patterson KI et al (2009) Dual-specificity phosphatases: critical regulators with diverse cellular targets. Biochem J 418(3):475–489CrossRefPubMedGoogle Scholar
  202. 202.
    Xu S et al (2005) Abrogation of DUSP6 by hypermethylation in human pancreatic cancer. J Hum Genet 50(4):159–167CrossRefGoogle Scholar
  203. 203.
    Hill R et al (2010) PTEN loss accelerates KrasG12D-induced pancreatic cancer development. Cancer Res 70(18):7114–7124CrossRefPubMedPubMedCentralGoogle Scholar
  204. 204.
    Zeleniak AE et al (2018) PTEN-dependent stabilization of MTSS1 inhibits metastatic phenotype in pancreatic ductal adenocarcinoma. Neoplasia 20(1):12–24CrossRefPubMedGoogle Scholar
  205. 205.
    Wartenberg M et al (2016) PTEN alterations of the stromal cells characterise an aggressive subpopulation of pancreatic cancer with enhanced metastatic potential. Eur J Cancer 65:80–90CrossRefPubMedGoogle Scholar
  206. 206.
    Jiang ZX, Zhang ZY (2008) Targeting PTPs with small molecule inhibitors in cancer treatment. Cancer Metastasis Rev 27(2):263–272CrossRefPubMedPubMedCentralGoogle Scholar
  207. 207.
    Heneberg P (2009) Use of protein tyrosine phosphatase inhibitors as promising targeted therapeutic drugs. Curr Med Chem 16(6):706–733CrossRefPubMedGoogle Scholar
  208. 208.
    Blaskovich MA (2009) Drug discovery and protein tyrosine phosphatases. Curr Med Chem 16(17):2095–2176CrossRefPubMedGoogle Scholar
  209. 209.
    Zhang ZY (2017) Drugging the undruggable: therapeutic potential of targeting protein tyrosine phosphatases. Acc Chem Res 50(1):122–129CrossRefPubMedGoogle Scholar
  210. 210.
    Xie L et al (2003) Cellular effects of small molecule PTP1B inhibitors on insulin signaling. Biochemistry 42(44):12792–12804CrossRefPubMedGoogle Scholar
  211. 211.
    Boutselis IG et al (2007) Synthesis and cell-based activity of a potent and selective protein tyrosine phosphatase 1B inhibitor prodrug. J Med Chem 50(4):856–864CrossRefPubMedGoogle Scholar
  212. 212.
    Erbe DV et al (2005) Ertiprotafib improves glycemic control and lowers lipids via multiple mechanisms. Mol Pharmacol 67(1):69–77CrossRefPubMedGoogle Scholar
  213. 213.
    Lantz KA et al (2010) Inhibition of PTP1B by trodusquemine (MSI-1436) causes fat-specific weight loss in diet-induced obese mice. Obesity (Silver Spring) 18(8):1516–1523CrossRefGoogle Scholar
  214. 214.
    Haque A et al (2011) Conformation-sensing antibodies stabilize the oxidized form of PTP1B and inhibit its phosphatase activity. Cell 147(1):185–198CrossRefPubMedPubMedCentralGoogle Scholar
  215. 215.
    Bentires-Alj M et al (2004) Activating mutations of the Noonan syndrome-associated SHP2/PTPN11 gene in human solid tumors and adult acute myelogenous leukemia. Cancer Res 64(24):8816–8820CrossRefPubMedGoogle Scholar
  216. 216.
    Chan G, Kalaitzidis D, Neel BG (2008) The tyrosine phosphatase Shp2 (PTPN11) in cancer. Cancer Metastasis Rev 27(2):179–192CrossRefPubMedGoogle Scholar
  217. 217.
    Zeng LF et al (2014) Therapeutic potential of targeting the oncogenic SHP2 phosphatase. J Med Chem 57(15):6594–6609CrossRefPubMedPubMedCentralGoogle Scholar
  218. 218.
    Zhang RY et al (2016) SHP2 phosphatase as a novel therapeutic target for melanoma treatment. Oncotarget 7(45):73817–73829PubMedPubMedCentralGoogle Scholar
  219. 219.
    Hof P et al (1998) Crystal structure of the tyrosine phosphatase SHP-2. Cell 92(4):441–450CrossRefPubMedGoogle Scholar
  220. 220.
    Pluskey S et al (1995) Potent stimulation of SH-PTP2 phosphatase activity by simultaneous occupancy of both SH2 domains. J Biol Chem 270(7):2897–2900CrossRefPubMedGoogle Scholar
  221. 221.
    Chen YN et al (2016) Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases. Nature 535(7610):148–152CrossRefPubMedGoogle Scholar
  222. 222.
    Daouti S et al (2008) A selective phosphatase of regenerating liver phosphatase inhibitor suppresses tumor cell anchorage-independent growth by a novel mechanism involving p130Cas cleavage. Cancer Res 68(4):1162–1169CrossRefPubMedGoogle Scholar
  223. 223.
    Hoeger B et al (2014) Biochemical evaluation of virtual screening methods reveals a cell-active inhibitor of the cancer-promoting phosphatases of regenerating liver. Eur J Med Chem 88:89–100CrossRefPubMedPubMedCentralGoogle Scholar
  224. 224.
    Sun JP et al (2007) Phosphatase activity, trimerization, and the C-terminal polybasic region are all required for PRL1-mediated cell growth and migration. J Biol Chem 282(39):29043–29051CrossRefPubMedGoogle Scholar
  225. 225.
    Jeong DG et al (2005) Trimeric structure of PRL-1 phosphatase reveals an active enzyme conformation and regulation mechanisms. J Mol Biol 345(2):401–413CrossRefPubMedGoogle Scholar
  226. 226.
    Sun JP et al (2005) Structure and biochemical properties of PRL-1, a phosphatase implicated in cell growth, differentiation, and tumor invasion. Biochemistry 44(36):12009–12021CrossRefPubMedGoogle Scholar
  227. 227.
    Bai Y et al (2016) Novel anticancer agents based on targeting the trimer interface of the PRL phosphatase. Cancer Res 76(16):4805–4815CrossRefPubMedPubMedCentralGoogle Scholar
  228. 228.
    Wang HY, Cheng Z, Malbon CC (2003) Overexpression of mitogen-activated protein kinase phosphatases MKP1, MKP2 in human breast cancer. Cancer Lett 191(2):229–237CrossRefPubMedGoogle Scholar
  229. 229.
    Rojo F et al (2009) Mitogen-activated protein kinase phosphatase-1 in human breast cancer independently predicts prognosis and is repressed by doxorubicin. Clin Cancer Res 15(10):3530–3539CrossRefPubMedPubMedCentralGoogle Scholar
  230. 230.
    Farooq A, Zhou MM (2004) Structure and regulation of MAPK phosphatases. Cell Signal 16(7):769–779CrossRefPubMedGoogle Scholar
  231. 231.
    Molina G et al (2009) Zebrafish chemical screening reveals an inhibitor of Dusp6 that expands cardiac cell lineages. Nat Chem Biol 5(9):680–687CrossRefPubMedPubMedCentralGoogle Scholar
  232. 232.
    Wu QN et al (2018) Pharmacological inhibition of DUSP6 suppresses gastric cancer growth and metastasis and overcomes cisplatin resistance. Cancer Lett 412:243–255CrossRefPubMedGoogle Scholar
  233. 233.
    Shin JW et al. (2018) BCI induces apoptosis via generation of reactive oxygen species and activation of intrinsic mitochondrial pathway in H1299 lung cancer cells. Sci China Life Sci 61(10):1243–1253CrossRefPubMedGoogle Scholar
  234. 234.
    Korotchenko VN et al (2014) In vivo structure-activity relationship studies support allosteric targeting of a dual specificity phosphatase. ChemBioChem 15(10):1436–1445CrossRefPubMedPubMedCentralGoogle Scholar
  235. 235.
    Kaltenmeier CT et al (2017) A tumor cell-selective inhibitor of mitogen-activated protein kinase phosphatases sensitizes breast cancer cells to lymphokine-activated killer cell activity. J Pharmacol Exp Ther 361(1):39–50CrossRefPubMedPubMedCentralGoogle Scholar
  236. 236.
    Shrestha S et al (2007) PTP1B inhibitor ertiprotafib is also a potent inhibitor of IkappaB kinase beta (IKK-beta). Bioorg Med Chem Lett 17(10):2728–2730CrossRefPubMedGoogle Scholar
  237. 237.
    Wrobel J et al (1999) PTP1B inhibition and antihyperglycemic activity in the ob/ob mouse model of novel 11-arylbenzo[b]naphtho[2,3-d]furans and 11-arylbenzo[b]naphtho[2,3-d]thiophenes. J Med Chem 42(17):3199–3202CrossRefPubMedGoogle Scholar
  238. 238.
    Krishnan N et al (2014) Targeting the disordered C terminus of PTP1B with an allosteric inhibitor. Nat Chem Biol 10(7):558–566CrossRefPubMedPubMedCentralGoogle Scholar
  239. 239.
    Stanford SM, Bottini N (2017) Targeting tyrosine phosphatases: time to end the stigma. Trends Pharmacol Sci 38(6):524–540CrossRefPubMedPubMedCentralGoogle Scholar
  240. 240.
    Karisch R et al (2011) Global proteomic assessment of the classical protein-tyrosine phosphatome and “Redoxome”. Cell 146(5):826–840CrossRefPubMedPubMedCentralGoogle Scholar
  241. 241.
    Shojaee S et al (2015) Erk negative feedback control enables pre-B cell transformation and represents a therapeutic target in acute lymphoblastic leukemia. Cancer Cell 28(1):114–128CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Genetics, Ribeirão Preto Medical SchoolUniversity of São PauloRibeirão PretoBrazil

Personalised recommendations