Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


  • Nicholas R. LeslieEmail author
  • Laura Spinelli
  • Georgios Zilidis
  • Nimmi R. Weerasinghe
  • Priyanka Tibarewal
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_349



Historical Background

Widespread interest was generated in 1997 when PTEN was identified almost simultaneously by three research groups as a candidate tumor suppressor in cancers of the brain, prostate, and breast (Li and Sun 1997; Li et al. 1997; Steck et al. 1997). As a member of the large and diverse protein tyrosine phosphatase superfamily, it was expected that PTEN would act to oppose oncogenic tyrosine kinase signaling pathways by dephosphorylating specific tyrosine phosphorylated substrates. However, it soon emerged that PTEN is primarily a lipid phosphatase and that by dephosphorylating the lipid second messenger PtdIns(3,4,5)P 3, it acts to suppress signaling through the PI3K signaling pathway (Maehama and Dixon 1998) (Fig. 1). Here the substantial insight that has been provided in the last 13 years by the intensive study of this important tumor suppressor will be discussed.
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  1. Chalhoub N, Baker SJ. PTEN and the PI3-kinase pathway in cancer. Annu Rev Pathol. 2009;4:127–50.PubMedPubMedCentralCrossRefGoogle Scholar
  2. Chang N, El-Hayek YH, Gomez E, Wan Q. Phosphatase PTEN in neuronal injury and brain disorders. Trends Neurosci. 2007;30:581–6.CrossRefPubMedGoogle Scholar
  3. Garcia-Echeverria C, Sellers WR. Drug discovery approaches targeting the PI3K/Akt pathway in cancer. Oncogene. 2008;27:5511–26.CrossRefPubMedGoogle Scholar
  4. Hawkins PT, Anderson KE, Davidson K, Stephens LR. Signalling through Class I PI3Ks in mammalian cells. Biochem Soc Trans. 2006;34:647–62.CrossRefPubMedGoogle Scholar
  5. Keniry M, Parsons R. The role of PTEN signaling perturbations in cancer and in targeted therapy. Oncogene. 2008;27:5477–85.CrossRefPubMedGoogle Scholar
  6. Lee JO, Yang H, Georgescu MM, Di Cristofano A, Maehama T, Shi Y, et al. Crystal structure of the PTEN tumor suppressor: implications for its phosphoinositide phosphatase activity and membrane association. Cell. 1999;99:323–34.CrossRefPubMedGoogle Scholar
  7. Leslie NR, Batty IH, Maccario H, Davidson L, Downes CP. Understanding PTEN regulation: PIP2, polarity and protein stability. Oncogene. 2008;27:5464–76.CrossRefPubMedGoogle Scholar
  8. Li DM, Sun H. TEP1, encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor beta. Cancer Res. 1997;57:2124–9.PubMedGoogle Scholar
  9. 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;275:1943–7.CrossRefPubMedGoogle Scholar
  10. Maccario H, Perera NM, Gray A, Downes CP, Leslie NR. Ubiquitination of PTEN (phosphatase and tensin homolog) inhibits phosphatase activity and is enhanced by membrane targeting and hyperosmotic stress. J Biol Chem. 2010;285:12620–8.PubMedPubMedCentralCrossRefGoogle Scholar
  11. Maehama T, Dixon JE. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem. 1998;273:13375–8.CrossRefPubMedGoogle Scholar
  12. Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell. 2007;129:1261–74.PubMedPubMedCentralCrossRefGoogle Scholar
  13. Myers MP, Stolarov JP, Eng C, Li J, Wang SIMHW, et al. PTEN, the tumor suppressor from human chromosome 10q23, is a dual-specificity phosphatase. Proc Natl Acad Sci USA. 1997;94:9052–7.PubMedPubMedCentralCrossRefGoogle Scholar
  14. Oudit GY, Penninger JM. Cardiac regulation by phosphoinositide 3-kinases and PTEN. Cardiovasc Res. 2009;82:250–60.CrossRefPubMedGoogle Scholar
  15. Plum L, Ma X, Hampel B, Balthasar N, Coppari R, Munzberg H, et al. Enhanced PIP3 signaling in POMC neurons causes KATP channel activation and leads to diet-sensitive obesity. J Clin Invest. 2006;116:1886–901.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Ross AH, Gericke A. Phosphorylation keeps PTEN phosphatase closed for business. Proc Natl Acad Sci USA. 2009;106:1297–8.PubMedPubMedCentralCrossRefGoogle Scholar
  17. Salmena L, Carracedo A, Pandolfi PP. Tenets of PTEN tumor suppression. Cell. 2008;133:403–14.CrossRefPubMedGoogle Scholar
  18. 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;15:356–62.CrossRefPubMedGoogle Scholar
  19. Suzuki A, Nakano T, Mak TW, Sasaki T. Portrait of PTEN: messages from mutant mice. Cancer Sci. 2008;99:209–13.CrossRefPubMedGoogle Scholar
  20. Vanhaesebroeck B, Guillermet-Guibert J, Graupera M, Bilanges B. The emerging mechanisms of isoform-specific PI3K signalling. Nat Rev Mol Cell Biol. 2010;11:329–41.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Nicholas R. Leslie
    • 1
    Email author
  • Laura Spinelli
    • 1
  • Georgios Zilidis
    • 1
  • Nimmi R. Weerasinghe
    • 1
  • Priyanka Tibarewal
    • 1
  1. 1.Division of Cell Signalling and Immunology, College of Life SciencesUniversity of Dundee, Wellcome Trust BiocentreDundeeUK