Targeting PTEN in Colorectal Cancers

  • Larissa Kotelevets
  • Mark G. H. Scott
  • Eric ChastreEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1110)


Phosphatase and tensin homolog (PTEN) is a tumour suppressor that represents one of the most common targets for genetic defect in human cancer. PTEN controls an array of physiopathological processes related to cell proliferation, differentiation, DNA/chromosome integrity, apoptosis and invasiveness. PTEN dephosphorylates not only proteins, but also phosphoinositides generated by phosphatidylinositol 3-kinase, thus counteracting the Akt signalling pathway. Interestingly, PTEN can also exert some biological functions independently of its catalytic activity.

A feature of colorectal cancers is the relatively low incidence of PTEN mutation or deletion, whereas PTEN downregulation occurs in approximately one third of tumours. PTEN inactivation may be even higher when changes in posttranslational modifications and/or mislocalization of the tumour suppressor are accounted for. Strategies based on pharmacologically-induced restoration of wild-type PTEN function in colon cancer cells could therefore be considered, to impact cell growth, trigger apoptosis, and sensitize tumour cells to therapeutic agents.

This review details current knowledge of the mechanisms regulating PTEN expression, activity and function. It also focuses on the use of small molecules targeting positive or negative PTEN regulators and summarizes alternative strategies that could be used to alter PTEN conformation/activity. Finally, we propose an outline of a personalized approach to restore PTEN function in colon cancer cells.


AKT signaling DNA repair Molecular scaffolds Phosphatase Tumor suppressor 



This work was supported by the Centre National de la Recherche Scientifique and Institut National de la Santé et de la Recherche Médicale. Work in the group of MGHS is also supported by the Ligue Contre le Cancer (comité de l’Oise) and the Who am I? laboratory of excellence (grant ANR-11-LABX-0071) funded by the “Investments for the Future” program operated by The French National Research Agency (grant ANR-11-IDEX-0005-01).


  1. Aarts M, Liu Y, Liu L et al (2002) Treatment of ischemic brain damage by perturbing NMDA receptor-PSD-95 protein interactions. Science 298:846–850. CrossRefPubMedGoogle Scholar
  2. Al-Khouri AM, Ma Y, Togo SH et al (2005) Cooperative phosphorylation of the tumor suppressor phosphatase and tensin homologue (PTEN) by casein kinases and glycogen synthase kinase 3beta. J Biol Chem 280:35195–35202. CrossRefPubMedGoogle Scholar
  3. Arkin MR, Wells JA (2004) Small-molecule inhibitors of protein–protein interactions: progressing towards the dream. Nat Rev Drug Discov 3:301–317. CrossRefPubMedGoogle Scholar
  4. Arkin MR, Tang Y, Wells JA (2014) Small-molecule inhibitors of protein-protein interactions: progressing toward the reality. Chem Biol 21:1102–1114. CrossRefPubMedPubMedCentralGoogle Scholar
  5. Benoit YD, Witherspoon MS, Laursen KB et al (2013) Pharmacological inhibition of polycomb repressive complex-2 activity induces apoptosis in human colon cancer stem cells. Exp Cell Res 319:1463–1470. CrossRefPubMedGoogle Scholar
  6. Berg T (2003) Modulation of protein–protein interactions with small organic molecules. Angew Chem Int Ed Engl 42:2462–2481. CrossRefPubMedGoogle Scholar
  7. Bolduc D, Rahdar M, Tu-Sekine B et al (2013) Phosphorylation-mediated PTEN conformational closure and deactivation revealed with protein semisynthesis. eLife 2:e00691. CrossRefPubMedPubMedCentralGoogle Scholar
  8. Buontempo F, Orsini E, Martins LR et al (2014) Cytotoxic activity of the casein kinase 2 inhibitor CX-4945 against T-cell acute lymphoblastic leukemia: targeting the unfolded protein response signaling. Leukemia 28:543–553. CrossRefPubMedGoogle Scholar
  9. Cancer Genome Atlas Research Network (2012) Comprehensive molecular characterization of human colon and rectal cancer. Nature 487:330–337. CrossRefGoogle Scholar
  10. Carpten JD, Faber AL, Horn C et al (2007) A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature 448:439–444. CrossRefPubMedGoogle Scholar
  11. Carracedo A, Alimonti A, Pandolfi PP (2011) PTEN level in tumor suppression: how much is too little? Cancer Res 71:629–633. CrossRefPubMedPubMedCentralGoogle Scholar
  12. Chagpar RB, Links PH, Pastor MC et al (2010) Direct positive regulation of PTEN by the p85 subunit of phosphatidylinositol 3-kinase. Proc Natl Acad Sci U S A 107:5471–5476. CrossRefPubMedPubMedCentralGoogle Scholar
  13. Chang TC, Mikheev AM, Huynh W et al (2014) Parallel microfluidic chemosensitivity testing on individual slice cultures. Lab Chip 14:4540–4551. CrossRefPubMedPubMedCentralGoogle Scholar
  14. Chastre E, Abdessamad M, Kruglov A et al (2009) TRIP6, a novel molecular partner of the MAGI-1 scaffolding molecule, promotes invasiveness. FASEB J 23:916–928. CrossRefPubMedGoogle Scholar
  15. Chen J, Wang W, Zhang Y et al (2014) The roles of miR-200c in colon cancer and associated molecular mechanisms. Tumor Biol 35:6475–6483. CrossRefGoogle Scholar
  16. Chen J-H, Zhang P, Chen W-D et al (2015) ATM-mediated PTEN phosphorylation promotes PTEN nuclear translocation and autophagy in response to DNA-damaging agents in cancer cells. Autophagy 11:239–252. CrossRefPubMedPubMedCentralGoogle Scholar
  17. Cheung LWT, Walkiewicz KW, Besong TMD et al (2015) Regulation of the PI3K pathway through a p85α monomer-homodimer equilibrium. elife 4:e06866. CrossRefPubMedPubMedCentralGoogle Scholar
  18. Chisanga D, Keerthikumar S, Pathan M et al (2016) Colorectal cancer atlas: an integrative resource for genomic and proteomic annotations from colorectal cancer cell lines and tissues. Nucleic Acids Res 44:D969–D974. CrossRefPubMedGoogle Scholar
  19. Choi BH, Pagano M, Dai W (2014) Plk1 protein phosphorylates phosphatase and Tensin homolog (PTEN) and regulates its mitotic activity during the cell cycle. J Biol Chem 289:14066–14074. CrossRefPubMedPubMedCentralGoogle Scholar
  20. Colangelo T, Fucci A, Votino C et al (2013) MicroRNA-130b promotes tumor development and is associated with poor prognosis in colorectal cancer. Neoplasia 15:1086–1099. CrossRefPubMedPubMedCentralGoogle Scholar
  21. Cordier F, Chaffotte A, Terrien E et al (2012) Ordered phosphorylation events in two independent cascades of the PTEN C-tail revealed by NMR. J Am Chem Soc 134:20533–20543. CrossRefPubMedGoogle Scholar
  22. Das S, Dixon JE, Cho W (2003) Membrane-binding and activation mechanism of PTEN. Proc Natl Acad Sci U S A 100:7491–7496. CrossRefPubMedPubMedCentralGoogle Scholar
  23. Davidson L, Maccario H, Perera NM et al (2010) Suppression of cellular proliferation and invasion by the concerted lipid and protein phosphatase activities of PTEN. Oncogene 29:687–697. CrossRefPubMedGoogle Scholar
  24. Davies EJ, Marsh Durban V, Meniel V et al (2014) PTEN loss and KRAS activation leads to the formation of serrated adenomas and metastatic carcinoma in the mouse intestine. J Pathol 233:27–38. CrossRefPubMedGoogle Scholar
  25. Dev KK (2004) Making protein interactions druggable: targeting PDZ domains. Nat Rev Drug Discov 3:1047–1056. CrossRefPubMedGoogle Scholar
  26. Di Cristofano A, Pesce B, Cordon-Cardo C, Pandolfi PP (1998) Pten is essential for embryonic development and tumour suppression. Nat Genet 19:348–355. CrossRefPubMedGoogle Scholar
  27. Dillon LM, Miller TW (2014) Therapeutic targeting of cancers with loss of PTEN function. Curr Drug Targets 15:65–79. CrossRefPubMedPubMedCentralGoogle Scholar
  28. Eide PW, Cekaite L, Danielsen SA et al (2013) NEDD4 is overexpressed in colorectal cancer and promotes colonic cell growth independently of the PI3K/PTEN/AKT pathway. Cell Signal 25:12–18. CrossRefPubMedGoogle Scholar
  29. Escrivà M, Peiro S, Herranz N et al (2008) Repression of PTEN phosphatase by Snail1 transcriptional factor during gamma radiation-induced apoptosis. Mol Cell Biol 28:1528–1540. CrossRefPubMedPubMedCentralGoogle Scholar
  30. Fan D, Lin X, Zhang F et al (2018) MicroRNA 26b promotes colorectal cancer metastasis by downregulating phosphatase and tensin homolog and wingless-type MMTV integration site family member 5A. Cancer Sci 109:354–362. CrossRefPubMedGoogle Scholar
  31. Fearon ER, Vogelstein B (1990) A genetic model for colorectal tumorigenesis. Cell 61:759–767. CrossRefPubMedPubMedCentralGoogle Scholar
  32. Fine B, Hodakoski C, Koujak S et al (2009) Activation of the PI3K pathway in cancer through inhibition of PTEN by exchange factor P-REX2a. Science 325:1261–1265. CrossRefPubMedPubMedCentralGoogle Scholar
  33. Fragoso R, Barata JT (2015) Kinases, tails and more: regulation of PTEN function by phosphorylation. Methods 77-78:75–81. CrossRefPubMedGoogle Scholar
  34. Freeman DJ, Li AG, Wei G et al (2003) PTEN tumor suppressor regulates p53 protein levels and activity through phosphatase-dependent and -independent mechanisms. Cancer Cell 3:117–130. CrossRefPubMedGoogle Scholar
  35. Fridberg M, Servin A, Anagnostaki L et al (2007) Protein expression and cellular localization in two prognostic subgroups of diffuse large B-cell lymphoma: higher expression of ZAP70 and PKC-beta II in the non-germinal center group and poor survival in patients deficient in nuclear PTEN. Leuk Lymphoma 48:2221–2232. CrossRefPubMedGoogle Scholar
  36. Fujii N, Haresco JJ, Novak KAP et al (2003) A selective irreversible inhibitor targeting a PDZ protein interaction domain. J Am Chem Soc 125:12074–12075. CrossRefPubMedGoogle Scholar
  37. Fujii N, Haresco JJ, Novak KAP, Gage RM, Pedemonte N, Stokoe D, Kuntz ID, Kiplin Guy R (2007) Rational design of a nonpeptide general chemical scaffold for reversible inhibition of PDZ domain interactions. Bioorg Med Chem Lett 17(2):549–552CrossRefGoogle Scholar
  38. Furnari FB, Huang HJ, Cavenee WK (1998) The phosphoinositol phosphatase activity of PTEN mediates a serum-sensitive G1 growth arrest in glioma cells. Cancer Res 58:5002–5008PubMedGoogle Scholar
  39. Geng L, Sun B, Gao B et al (2014) MicroRNA-103 promotes colorectal Cancer by targeting tumor suppressor DICER and PTEN. Int J Mol Sci 15:8458–8472. CrossRefPubMedPubMedCentralGoogle Scholar
  40. Georgescu MM, Kirsch KH, Kaloudis P et al (2000) Stabilization and productive positioning roles of the C2 domain of PTEN tumor suppressor. Cancer Res 60:7033–7038PubMedGoogle Scholar
  41. Ghosh-Choudhury N, Mandal CC, Ghosh-Choudhury N, Ghosh Choudhury G (2010) Simvastatin induces derepression of PTEN expression via NFkappaB to inhibit breast cancer cell growth. Cell Signal 22:749–758. CrossRefPubMedPubMedCentralGoogle Scholar
  42. Goel A, Arnold CN, Niedzwiecki D et al (2004) Frequent inactivation of PTEN by promoter hypermethylation in microsatellite instability-high sporadic colorectal cancers. Cancer Res 64:3014–3021. CrossRefPubMedGoogle Scholar
  43. González-Santamaría J, Campagna M, Ortega-Molina A et al (2012) Regulation of the tumor suppressor PTEN by SUMO. Cell Death Dis 3:e393. CrossRefPubMedPubMedCentralGoogle Scholar
  44. Gu J, Tamura M, Yamada KM (1998) Tumor suppressor PTEN inhibits integrin- and growth factor-mediated mitogen-activated protein (MAP) kinase signaling pathways. J Cell Biol 143:1375–1383. CrossRefPubMedPubMedCentralGoogle Scholar
  45. Guinney J, Dienstmann R, Wang X et al (2015) The consensus molecular subtypes of colorectal cancer. Nat Med 21:1350–1356. CrossRefPubMedPubMedCentralGoogle Scholar
  46. Gumireddy K, Young DD, Xiong X et al (2008) Small-molecule inhibitors of MicroRNA miR-21 function. Angew Chem Int Ed Engl 47:7482–7484. CrossRefPubMedPubMedCentralGoogle Scholar
  47. Harris BZ, Lim WA (2001) Mechanism and role of PDZ domains in signaling complex assembly. J Cell Sci 114:3219–3231PubMedGoogle Scholar
  48. He L, Ingram A, Rybak AP, Tang D (2010) Shank-interacting protein–like 1 promotes tumorigenesis via PTEN inhibition in human tumor cells. J Clin Invest 120:2094–2108. CrossRefPubMedPubMedCentralGoogle Scholar
  49. He L, Fan C, Kapoor A et al (2011) α-Mannosidase 2C1 attenuates PTEN function in prostate cancer cells. Nat Commun 2:307. CrossRefPubMedGoogle Scholar
  50. Herlevsen M, Oxford G, Ptak C et al (2007) A novel model to identify interaction partners of the PTEN tumor suppressor gene in human bladder cancer. Biochem Biophys Res Commun 352:549–555. CrossRefPubMedGoogle Scholar
  51. Hesson LB, Packham D, Pontzer E et al (2012) A reinvestigation of somatic hypermethylation at the PTEN CpG island in cancer cell lines. Biol Proced Online 14:5. CrossRefPubMedPubMedCentralGoogle Scholar
  52. Hettinger K, Vikhanskaya F, Poh MK et al (2007) c-Jun promotes cellular survival by suppression of PTEN. Cell Death Differ 14:218–229. CrossRefPubMedGoogle Scholar
  53. Hopkins BD, Fine B, Steinbach N et al (2013) A secreted PTEN phosphatase that enters cells to alter signaling and survival. Science 341:399–402. CrossRefPubMedPubMedCentralGoogle Scholar
  54. Huang J, Yan J, Zhang J et al (2012) SUMO1 modification of PTEN regulates tumorigenesis by controlling its association with the plasma membrane. Nat Commun 3:911. CrossRefPubMedGoogle Scholar
  55. Ikenoue T, Inoki K, Zhao B, Guan KL (2008) PTEN acetylation modulates its interaction with PDZ domain. Cancer Res 68:6908–6912. CrossRefPubMedGoogle Scholar
  56. Javadi A, Deevi RK, Evergren E et al (2017) PTEN controls glandular morphogenesis through a juxtamembrane β-Arrestin1/ARHGAP21 scaffolding complex. eLife 6:e24578. CrossRefPubMedPubMedCentralGoogle Scholar
  57. Johnsson P, Ackley A, Vidarsdottir L et al (2013) A pseudogene long-noncoding-RNA network regulates PTEN transcription and translation in human cells. Nat Struct Mol Biol 20:440–446. CrossRefPubMedPubMedCentralGoogle Scholar
  58. Kim SS, Yoo NJ, Jeong EG et al (2008) Expression of NEDD4-1, a PTEN regulator, in gastric and colorectal carcinomas. APMIS 116:779–784. CrossRefPubMedGoogle Scholar
  59. Kim Y-C, Kitaura H, Taira T et al (2009) Oxidation of DJ-1-dependent cell transformation through direct binding of DJ-1 to PTEN. Int J Oncol 35:1331–1341. CrossRefPubMedGoogle Scholar
  60. Kotelevets L, van Hengel J, Bruyneel E et al (2001) The lipid phosphatase activity of PTEN is critical for stabilizing intercellular junctions and reverting invasiveness. J Cell Biol 155:1129–1136. CrossRefPubMedPubMedCentralGoogle Scholar
  61. Kotelevets L, van Hengel J, Bruyneel E et al (2005) Implication of the MAGI-1b/PTEN signalosome in stabilization of adherens junctions and suppression of invasiveness. FASEB J 19:115–117. CrossRefPubMedGoogle Scholar
  62. Kotelevets L, Chastre E, Desmaële D, Couvreur P (2016) Nanotechnologies for the treatment of colon cancer: from old drugs to new hope. Int J Pharm 514:24–40. CrossRefPubMedGoogle Scholar
  63. Kudinov AE, Karanicolas J, Golemis EA, Boumber Y (2017) Musashi RNA-binding proteins as Cancer drivers and novel therapeutic targets. Clin Cancer Res 23:2143–2153. CrossRefPubMedPubMedCentralGoogle Scholar
  64. Kwon J, Lee S-R, Yang K-S et al (2004) Reversible oxidation and inactivation of the tumor suppressor PTEN in cells stimulated with peptide growth factors. Proc Natl Acad Sci U S A 101:16419–16424. CrossRefPubMedPubMedCentralGoogle Scholar
  65. Lavictoire SJ, Gont A, Julian LM et al (2018) Engineering PTEN-L for cell-mediated delivery. Mol Ther Methods Clin Dev 9:12–22. CrossRefPubMedGoogle Scholar
  66. Leblanc BW, Iwata M, Mallon AP et al (2010) A cyclic peptide targeted against PSD-95 blocks central sensitization and attenuates thermal hyperalgesia. Neuroscience 167:490–500. CrossRefPubMedPubMedCentralGoogle Scholar
  67. Lee S-R, Yang K-S, Kwon J et al (2002) Reversible inactivation of the tumor suppressor PTEN by H2O2. J Biol Chem 277:20336–20342. CrossRefPubMedGoogle Scholar
  68. Lemmon MA (2007) Pleckstrin homology (PH) domains and phosphoinositides. Biochem Soc Symp 74:81–93. CrossRefGoogle Scholar
  69. Leslie NR, Bennett D, Lindsay YE et al (2003) Redox regulation of PI 3-kinase signalling via inactivation of PTEN. EMBO J 22:5501–5510. CrossRefPubMedPubMedCentralGoogle Scholar
  70. Leslie NR, Yang X, Downes CP, Weijer CJ (2007) PtdIns(3,4,5)P(3)-dependent and -independent roles for PTEN in the control of cell migration. Curr Biol 17:115–125. CrossRefPubMedPubMedCentralGoogle Scholar
  71. Li DM, Sun H (1997) TEP1, encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor beta. Cancer Res 57:2124–2129PubMedGoogle Scholar
  72. Li J, Yen C, Liaw D et al (1997) PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275:1943–1947. CrossRefPubMedGoogle Scholar
  73. Li Z, Dong X, Dong X et al (2005) Regulation of PTEN by Rho small GTPases. Nat Cell Biol 7:399–404. CrossRefPubMedGoogle Scholar
  74. Li N, Yousefi M, Nakauka-Ddamba A et al (2015) The Msi family of RNA-binding proteins function redundantly as intestinal oncoproteins. Cell Rep 13:2440–2455. CrossRefPubMedPubMedCentralGoogle Scholar
  75. Li Y, Sun J, Cai Y et al (2016) MiR-200a acts as an oncogene in colorectal carcinoma by targeting PTEN. Exp Mol Pathol 101:308–313. CrossRefPubMedGoogle Scholar
  76. Liang H, He S, Yang J et al (2014) PTENα, a PTEN isoform translated through alternative initiation, regulates mitochondrial function and energy metabolism. Cell Metab 19:836–848. CrossRefPubMedPubMedCentralGoogle Scholar
  77. Liang H, Chen X, Yin Q et al (2017) PTENβ is an alternatively translated isoform of PTEN that regulates rDNA transcription. Nat Commun 8:14771. CrossRefPubMedPubMedCentralGoogle Scholar
  78. Lima-Fernandes E, Enslen H, Camand E et al (2011) Distinct functional outputs of PTEN signalling are controlled by dynamic association with β-arrestins. EMBO J 30:2557–2568. CrossRefPubMedPubMedCentralGoogle Scholar
  79. Lima-Fernandes E, Misticone S, Boularan C et al (2014) A biosensor to monitor dynamic regulation and function of tumour suppressor PTEN in living cells. Nat Commun 5:4431. CrossRefPubMedGoogle Scholar
  80. Lin P-C, Lin J-K, Lin H-H et al (2015) A comprehensive analysis of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) loss in colorectal cancer. World J Surg Oncol 13:186. CrossRefPubMedPubMedCentralGoogle Scholar
  81. Loree JM, Pereira AA, Lam M et al (2018) Classifying colorectal cancer by tumor location rather than sidedness highlights a continuum in mutation profiles and consensus molecular subtypes. Clin Cancer Res 24:1062–1072. CrossRefPubMedGoogle Scholar
  82. Lu Y, Yu Q, Liu JH et al (2003) Src family protein-tyrosine kinases alter the function of PTEN to regulate phosphatidylinositol 3-kinase/AKT cascades. J Biol Chem 278:40057–40066. CrossRefPubMedGoogle Scholar
  83. Lubecka-Pietruszewska K, Kaufman-Szymczyk A, Stefanska B et al (2015) Sulforaphane alone and in combination with clofarabine epigenetically regulates the expression of DNA methylation-silenced tumour suppressor genes in human breast cancer cells. J Nutrigenet Nutrigenomics 8:91–101. CrossRefPubMedGoogle Scholar
  84. Marsh V, Winton DJ, Williams GT et al (2008) Epithelial Pten is dispensable for intestinal homeostasis but suppresses adenoma development and progression after Apc mutation. Nat Genet 40:1436–1444. CrossRefPubMedGoogle Scholar
  85. Meng Z, Jia L-F, Gan Y-H (2016) PTEN activation through K163 acetylation by inhibiting HDAC6 contributes to tumour inhibition. Oncogene 35:2333–2344. CrossRefPubMedGoogle Scholar
  86. Meuillet EJ, Mahadevan D, Berggren M et al (2004) Thioredoxin-1 binds to the C2 domain of PTEN inhibiting PTEN“s lipid phosphatase activity and membrane binding: a mechanism for the functional loss of PTEN”s tumor suppressor activity. Arch Biochem Biophys 429:123–133. CrossRefPubMedGoogle Scholar
  87. Misticone S, Lima-Fernandes E, Scott MGH (2016) Rapid detection of dynamic PTEN regulation in living cells using intramolecular BRET. Methods Mol Biol 1388:95–110. CrossRefPubMedGoogle Scholar
  88. Nagayama S, Iiizumi M, Katagiri T et al (2004) Identification of PDZK4, a novel human gene with PDZ domains, that is upregulated in synovial sarcomas. Oncogene 23:5551–5557. CrossRefPubMedGoogle Scholar
  89. Nakahata S, Ichikawa T, Maneesaay P et al (2014) Loss of NDRG2 expression activates PI3K-AKT signalling via PTEN phosphorylation in ATLL and other cancers. Nat Commun 5(3393):1–15. CrossRefGoogle Scholar
  90. Nakakido M, Deng Z, Suzuki T et al (2015) Dysregulation of AKT pathway by SMYD2-mediated lysine methylation on PTEN. Neoplasia 17:367–373. CrossRefPubMedPubMedCentralGoogle Scholar
  91. Nguyen D-D, Chang S (2018) Development of novel therapeutic agents by inhibition of oncogenic microRNAs. Int J Mol Sci 19:65. CrossRefGoogle Scholar
  92. Nguyen H-N, Yang J-M, Afkari Y et al (2014) Engineering ePTEN, an enhanced PTEN with increased tumor suppressor activities. Proc Natl Acad Sci U S A 111:E2684–E2693. CrossRefPubMedPubMedCentralGoogle Scholar
  93. Nguyen H-N, Yang J-M, Miyamoto T et al (2015) Opening the conformation is a master switch for the dual localization and phosphatase activity of PTEN. Sci Rep 5:12600. CrossRefPubMedPubMedCentralGoogle Scholar
  94. Numajiri N, Takasawa K, Nishiya T et al (2011) On-off system for PI3-kinase-Akt signaling through S-nitrosylation of phosphatase with sequence homology to tensin (PTEN). Proc Natl Acad Sci U S A 108:10349–10354. CrossRefPubMedPubMedCentralGoogle Scholar
  95. Odriozola L, Singh G, Hoang T, Chan AM (2007) Regulation of PTEN activity by its carboxyl-terminal autoinhibitory domain. J Biol Chem 282:23306–23315. CrossRefPubMedGoogle Scholar
  96. Okahara F, Ikawa H, Kanaho Y, Maehama T (2004) Regulation of PTEN phosphorylation and stability by a tumor suppressor candidate protein. J Biol Chem 279:45300–45303. CrossRefPubMedGoogle Scholar
  97. Okumura K, Zhao M, Depinho RA et al (2005) Cellular transformation by the MSP58 oncogene is inhibited by its physical interaction with the PTEN tumor suppressor. Proc Natl Acad Sci U S A 102:2703–2706. CrossRefPubMedPubMedCentralGoogle Scholar
  98. Okumura K, Mendoza M, Bachoo RM et al (2006) PCAF modulates PTEN activity. J Biol Chem 281:26562–26568. CrossRefPubMedGoogle Scholar
  99. Papa A, Wan L, Bonora M et al (2014) Cancer-associated PTEN mutants act in a dominant-negative manner to suppress PTEN protein function. Cell 157:595–610. CrossRefPubMedPubMedCentralGoogle Scholar
  100. Park J-H, Lin M-L, Nishidate T et al (2006) PDZ-binding kinase/T-LAK cell-originated protein kinase, a putative cancer/testis antigen with an oncogenic activity in breast cancer. Cancer Res 66:9186–9195. CrossRefPubMedGoogle Scholar
  101. Patel L, Pass I, Coxon P et al (2001) Tumor suppressor and anti-inflammatory actions of PPARgamma agonists are mediated via upregulation of PTEN. Curr Biol 11:764–768. CrossRefPubMedGoogle Scholar
  102. Perren A, Komminoth P, Saremaslani P et al (2000) Mutation and expression analyses reveal differential subcellular compartmentalization of PTEN in endocrine pancreatic tumors compared to normal islet cells. Am J Pathol 157:1097–1103. CrossRefPubMedPubMedCentralGoogle Scholar
  103. Podsypanina K, Ellenson LH, Nemes A et al (1999) Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems. Proc Natl Acad Sci U S A 96:1563–1568. CrossRefPubMedPubMedCentralGoogle Scholar
  104. Poliseno L, Salmena L, Zhang J et al (2010) A coding-independent function of gene and pseudogene mRNAs regulates tumour biology. Nature 465:1033–1038. CrossRefPubMedPubMedCentralGoogle Scholar
  105. Pulido R, Baker SJ, Barata JT et al (2014) A unified nomenclature and amino acid numbering for human PTEN. Sci Signal 7:pe15. CrossRefPubMedPubMedCentralGoogle Scholar
  106. Qin Y, Huo Z, Song X et al (2018) mir-106a regulates cell proliferation and apoptosis of colon cancer cells through targeting the PTEN/PI3K/AKT signaling pathway. Oncol Lett 15:3197–3201. CrossRefPubMedGoogle Scholar
  107. Rabinovsky R, Pochanard P, McNear C et al (2009) p85 associates with Unphosphorylated PTEN and the PTEN-associated complex. Mol Cell Biol 29:5377–5388. CrossRefPubMedPubMedCentralGoogle Scholar
  108. Raftopoulou M, Etienne-Manneville S, Self A et al (2004) Regulation of cell migration by the C2 domain of the tumor suppressor PTEN. Science 303:1179–1181. CrossRefPubMedGoogle Scholar
  109. Rahdar M, Inoue T, Meyer T et al (2009) A phosphorylation-dependent intramolecular interaction regulates the membrane association and activity of the tumor suppressor PTEN. Proc Natl Acad Sci U S A 106:480–485. CrossRefPubMedGoogle Scholar
  110. Sangodkar J, Perl A, Tohme R et al (2017) Activation of tumor suppressor protein PP2A inhibits KRAS-driven tumor growth. J Clin Invest 127:2081–2090. CrossRefPubMedPubMedCentralGoogle Scholar
  111. Shao J, Washington MK, Saxena R, Sheng H (2007) Heterozygous disruption of the PTEN promotes intestinal neoplasia in APCmin/+ mouse: roles of osteopontin. Carcinogenesis 28:2476–2483. CrossRefPubMedGoogle Scholar
  112. Shen YH, Zhang L, Gan Y et al (2006) Up-regulation of PTEN (phosphatase and tensin homolog deleted on chromosome ten) mediates p38 MAPK stress signal-induced inhibition of insulin signaling. A cross-talk between stress signaling and insulin signaling in resistin-treated human endothelial cells. J Biol Chem 281:7727–7736. CrossRefPubMedGoogle Scholar
  113. Shen WH, Balajee AS, Wang J et al (2007) Essential role for nuclear PTEN in maintaining chromosomal integrity. Cell 128:157–170. CrossRefPubMedGoogle Scholar
  114. Shi Y, Wang J, Chandarlapaty S et al (2014) PTEN is a protein tyrosine phosphatase for IRS1. Nat Struct Mol Biol 21:522–527. CrossRefPubMedPubMedCentralGoogle Scholar
  115. Shnitsar I, Bashkurov M, Masson GR et al (2015) PTEN regulates cilia through Dishevelled. Nat Commun 6:8388. CrossRefPubMedPubMedCentralGoogle Scholar
  116. Silva A, Yunes JA, Cardoso BA et al (2008) PTEN posttranslational inactivation and hyperactivation of the PI3K/Akt pathway sustain primary T cell leukemia viability. J Clin Invest 118:3762–3774. CrossRefPubMedPubMedCentralGoogle Scholar
  117. Song MS, Salmena L, Carracedo A et al (2008) The deubiquitinylation and localization of PTEN are regulated by a HAUSP-PML network. Nature 455:813–817. CrossRefPubMedPubMedCentralGoogle Scholar
  118. Song MS, Carracedo A, Salmena L et al (2011) Nuclear PTEN regulates the APC-CDH1 tumor-suppressive complex in a phosphatase-independent manner. Cell 144:187–199. CrossRefPubMedPubMedCentralGoogle Scholar
  119. Song B, Long Y, Liu D et al (2017) MicroRNA-582 promotes tumorigenesis by targeting phosphatase and tensin homologue in colorectal cancer. Int J Mol Med 40:867–874. CrossRefPubMedGoogle Scholar
  120. Stambolic V, MacPherson D, Sas D et al (2001) Regulation of PTEN transcription by p53. Mol Cell 8:317–325. CrossRefPubMedGoogle Scholar
  121. Steck PA, Pershouse MA, Jasser SA et al (1997) Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet 15:356–362. CrossRefPubMedGoogle Scholar
  122. Sun H-B, Chen XI, Ji H et al (2014) miR-494 is an independent prognostic factor and promotes cell migration and invasion in colorectal cancer by directly targeting PTEN. Int J Oncol 45:2486–2494. CrossRefPubMedGoogle Scholar
  123. Sun J, Zhou J, Dong M, Sheng W (2017) Dysregulation of MicroRNA-543 expression in colorectal cancer promotes tumor migration and invasion. Mol Carcinog 56:250–257. CrossRefGoogle Scholar
  124. Suzuki A, de la Pompa JL, Stambolic V et al (1998) High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor gene in mice. Curr Biol 8:1169–1178. CrossRefGoogle Scholar
  125. Szado T, Vanderheyden V, Parys JB, De Smedt H, Rietdorf K, Kotelevets L, Chastre E, Khan F, Landegren U, Soderberg O, Bootman MD, Roderick HL (2008) Phosphorylation of inositol 1,4,5-trisphosphate receptors by protein kinase B/Akt inhibits Ca2+ release and apoptosis. Proc Natl Acad Sci 105(7):2427–2432CrossRefGoogle Scholar
  126. Tachibana M, Shibakita M, Ohno S et al (2002) Expression and prognostic significance of PTEN product protein in patients with esophageal squamous cell carcinoma. Cancer 94:1955–1960. CrossRefPubMedGoogle Scholar
  127. Tanaka R, Tomosugi M, Sakai T, Sowa Y (2016) MEK inhibitor suppresses expression of the miR-17-92 cluster with G1-phase arrest in HT-29 human colon cancer cells and MIA PaCa-2 pancreatic cancer cells. Anticancer Res 36:4537–4543. CrossRefPubMedGoogle Scholar
  128. Tang Y, Eng C (2006) PTEN autoregulates its expression by stabilization of p53 in a phosphatase-independent manner. Cancer Res 66:736–742. CrossRefPubMedGoogle Scholar
  129. Teng DH, Hu R, Lin H et al (1997) MMAC1/PTEN mutations in primary tumor specimens and tumor cell lines. Cancer Res 57:5221–5225PubMedGoogle Scholar
  130. Tibarewal P, Zilidis G, Spinelli L et al (2012) PTEN protein phosphatase activity correlates with control of gene expression and invasion, a tumor-suppressing phenotype, but not with AKT activity. Sci Signal 5:ra18. CrossRefPubMedGoogle Scholar
  131. Torres J, Pulido R (2001) The tumor suppressor PTEN is phosphorylated by the protein kinase CK2 at its C terminus. J Biol Chem 276:993–998. CrossRefPubMedGoogle Scholar
  132. Trotman LC, Wang X, Alimonti A et al (2007) Ubiquitination regulates PTEN nuclear import and tumor suppression. Cell 128:141–156. CrossRefPubMedPubMedCentralGoogle Scholar
  133. Tzani I, Ivanov IP, Andreev DE et al (2016) Systematic analysis of the PTEN5′ leader identifies a major AUU initiated proteoform. Open Biol 6:150203. CrossRefPubMedPubMedCentralGoogle Scholar
  134. Tzenaki N, Aivaliotis M, Papakonstanti EA (2015) Focal adhesion kinase phosphorylates the phosphatase and tensin homolog deleted on chromosome 10 under the control of p110δ phosphoinositide-3 kinase. FASEB J 29:4840–4852. CrossRefPubMedGoogle Scholar
  135. Uygur B, Abramo K, Leikina E et al (2015) SLUG is a direct transcriptional repressor of PTEN tumor suppressor. Prostate 75:907–916. CrossRefPubMedPubMedCentralGoogle Scholar
  136. Valiente M, Andrés-Pons A, Gomar B et al (2005) Binding of PTEN to specific PDZ domains contributes to PTEN protein stability and phosphorylation by microtubule-associated serine/threonine kinases. J Biol Chem 280:28936–28943. CrossRefPubMedGoogle Scholar
  137. Vazquez F, Ramaswamy S, Nakamura N, Sellers WR (2000) Phosphorylation of the PTEN tail regulates protein stability and function. Mol Cell Biol 20:5010–5018. CrossRefPubMedPubMedCentralGoogle Scholar
  138. Vazquez F, Grossman SR, Takahashi Y et al (2001) Phosphorylation of the PTEN tail acts as an inhibitory switch by preventing its recruitment into a protein complex. J Biol Chem 276:48627–48630. CrossRefPubMedGoogle Scholar
  139. Virolle T, Adamson ED, Baron V et al (2001) The Egr-1 transcription factor directly activates PTEN during irradiation-induced signalling. Nat Cell Biol 3:1124–1128. CrossRefPubMedGoogle Scholar
  140. Wang X, Trotman LC, Koppie T et al (2007) NEDD4-1 is a proto-oncogenic ubiquitin ligase for PTEN. Cell 128:129–139. CrossRefPubMedPubMedCentralGoogle Scholar
  141. Wang Q, Zhou Y, Jackson LN et al (2011) Nuclear factor of activated T cells (NFAT) signaling regulates PTEN expression and inestinal cell differentiation. Mol Biol Cell 22:412–420. CrossRefPubMedPubMedCentralGoogle Scholar
  142. Wang W, Chen Y, Wang S et al (2014) PIASxα ligase enhances SUMO1 modification of PTEN protein as a SUMO E3 ligase. J Biol Chem 289:3217–3230. CrossRefPubMedGoogle Scholar
  143. Wang S, Li N, Yousefi M et al (2015) Transformation of the intestinal epithelium by the MSI2 RNA-binding protein. Nat Commun 6:6517. CrossRefPubMedPubMedCentralGoogle Scholar
  144. Wang J, Xu J, Fu J et al (2016) MiR-29a regulates radiosensitivity in human intestinal cells by targeting PTEN gene. Radiat Res 186:292–301. CrossRefPubMedGoogle Scholar
  145. Wei Z, Cui L, Mei Z et al (2014) miR181a mediates metabolic shift in colon cancer cells via the PTEN/AKT pathway. FEBS Lett 588:1773–1779. CrossRefPubMedGoogle Scholar
  146. Whiteman DC, Zhou X-P, Cummings MC et al (2002) Nuclear PTEN expression and clinicopathologic features in a population-based series of primary cutaneous melanoma. Int J Cancer 99:63–67. CrossRefPubMedGoogle Scholar
  147. Wozniak DJ, Kajdacsy-Balla A, Macias V et al (2017) PTEN is a protein phosphatase that targets active PTK6 and inhibits PTK6 oncogenic signaling inprostate cancer. Nat Commun 8:1508. CrossRefPubMedPubMedCentralGoogle Scholar
  148. Wu W, Yang J, Feng X et al (2013) MicroRNA-32 (miR-32) regulates phosphatase and tensin homologue (PTEN) expression and promotes growth, migration, and invasion in colorectal carcinoma cells. Mol Cancer 12:30. CrossRefPubMedPubMedCentralGoogle Scholar
  149. Xia D, Srinivas H, Ahn Y-H et al (2007) Mitogen-activated protein kinase kinase-4 promotes cell survival by decreasing PTEN expression through an NF kappa B-dependent pathway. J Biol Chem 282:3507–3519. CrossRefPubMedGoogle Scholar
  150. Xia S-S, Zhang G-J, Liu Z-L et al (2017) MicroRNA-22 suppresses the growth, migration and invasion of colorectal cancer cells through a Sp1 negative feedback loop. Oncotarget 8:36266–36278. CrossRefPubMedPubMedCentralGoogle Scholar
  151. Xiang S, Fang J, Wang S et al (2015) MicroRNA-135b regulates the stability of PTEN and promotes glycolysis by targeting USP13 in human colorectal cancers. Oncol Rep 33:1342–1348. CrossRefPubMedGoogle Scholar
  152. Xiong Z, Guo M, Yu Y et al (2016) Downregulation of AIF by HIF-1 contributes to hypoxia-induced epithelial–mesenchymal transition of colon cancer. Carcinogenesis 37:1079–1088. CrossRefPubMedGoogle Scholar
  153. Xue Q, Sun K, Deng H-J et al (2013) Anti-miRNA-221 sensitizes human colorectal carcinoma cells to radiation by upregulating PTEN. World J Gastroenterol 19:9307–9317. CrossRefPubMedPubMedCentralGoogle Scholar
  154. Yang J-M, Schiapparelli P, Nguyen H-N et al (2017) Characterization of PTEN mutations in brain cancer reveals that pten mono-ubiquitination promotes protein stability and nuclear localization. Oncogene 36:3673–3685. CrossRefPubMedPubMedCentralGoogle Scholar
  155. Yazdani Y, Farazmandfar T, Azadeh H, Zekavatian Z (2016) The prognostic effect of PTEN expression status in colorectal cancer development and evaluation of factors affecting it: miR-21 and promoter methylation. J Biomed Sci 23:9. CrossRefPubMedPubMedCentralGoogle Scholar
  156. Yim E-K, Peng G, Dai H et al (2009) Rak functions as a tumor suppressor by regulating PTEN protein stability and function. Cancer Cell 15:304–314. CrossRefPubMedPubMedCentralGoogle Scholar
  157. Yu M, Trobridge P, Wang Y et al (2014) Inactivation of TGF-beta; signaling and loss of PTEN cooperate to induce colon cancer in vivo. Oncogene 33:1538–1547. CrossRefPubMedGoogle Scholar
  158. Zaric J, Joseph J-M, Tercier S et al (2012) Identification of MAGI1 as a tumor-suppressor protein induced by cyclooxygenase-2 inhibitors in colorectal cancer cells. Oncogene 31:48–59. CrossRefPubMedGoogle Scholar
  159. Zhang G, Gan Y-H (2017) Synergistic antitumor effects of the combined treatment with an HDAC6 inhibitor and a COX-2 inhibitor through activation of PTEN. Oncol Rep 38:2657–2666. CrossRefPubMedPubMedCentralGoogle Scholar
  160. Zhang G, Zhou H, Xiao H et al (2013) MicroRNA-92a functions as an oncogene in colorectal cancer by targeting PTEN. Dig Dis Sci 59:98–107. CrossRefPubMedGoogle Scholar
  161. Zhang L-L, Mu G-G, Ding Q-S et al (2015) Phosphatase and tensin homolog (PTEN) represses colon cancer progression through inhibiting paxillin transcription via PI3K/AKT/NF-κB pathway. J Biol Chem 290:15018–15029. CrossRefPubMedGoogle Scholar
  162. Zhang Z, Hou S-Q, He J et al (2016) PTEN regulates PLK1 and controls chromosomal stability during cell division. Cell Cycle 15:2476–2485. CrossRefPubMedPubMedCentralGoogle Scholar
  163. Zheng L, Zhang Y, Liu Y et al (2015) MiR-106b induces cell radioresistance. J Transl Med 13:252. CrossRefPubMedPubMedCentralGoogle Scholar
  164. Zhou X-P, Loukola A, Salovaara R et al (2002) PTEN mutational spectra, expression levels, and subcellular localization in microsatellite stable and unstable colorectal cancers. Am J Pathol 161:439–447. CrossRefPubMedPubMedCentralGoogle Scholar
  165. Zhou J, Wang J, Chen C et al (2018) USP7: target validation and drug discovery for cancer therapy. Med Chem 14:3–18. CrossRefPubMedGoogle Scholar
  166. Zhu J, Chen L, Zou L et al (2014) MiR-20b, -21, and -130b inhibit PTEN expression resulting in B7-H1 over-expression in advanced colorectal cancer. Hum Immunol 75:348–353. CrossRefPubMedGoogle Scholar
  167. Zou J, Luo H, Zeng Q et al (2011) Protein kinase CK2α is overexpressed in colorectal cancer and modulates cell proliferation and invasion via regulating EMT-related genes. J Transl Med 9:97. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Larissa Kotelevets
    • 1
    • 2
  • Mark G. H. Scott
    • 3
    • 4
  • Eric Chastre
    • 1
    • 2
    Email author
  1. 1.Inserm, UMR S 938, Cancer Biology and TherapeuticsCentre de Recherche Saint-AntoineParisFrance
  2. 2.Hôpital Saint-Antoine, Site Bâtiment Kourilsky, Université Pierre-et-Marie-Curie Paris 6Sorbonne UniversitésParisFrance
  3. 3.U1016, Institut Cochin, 27, CNRS, UMR8104Institut National de la Santé et de la RechercheMédicaleParisFrance
  4. 4.Université Paris DescartesSorbonne Paris CitéParisFrance

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