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PTEN  -  phosphatase and tensin homolog

Homo sapiens

 
 
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Disease relevance of PTEN

  • Mutations that impair PTEN function result in a marked increase in cellular levels of PIP3 and constitutive activation of Akt survival signaling pathways, leading to inhibition of apoptosis, hyperplasia, and tumor formation [1].
  • Frequent somatic mutations in PTEN and TP53 are mutually exclusive in the stroma of breast carcinomas [2].
  • Hereditary mutation of PTEN causes tumor-susceptibility diseases such as Cowden disease [3].
  • The PTEN and TSC2 tumor suppressors inhibit mammalian target of rapamycin (mTOR) signaling and are defective in distinct hamartoma syndromes [4].
  • In colon cancer cells, PTEN stimulates Cdx-2 protein expression and the transcriptional activity of the Cdx-2 promoter [5].
  • EF24 appears to have a potential therapeutic role in human ovarian cancer through the activation of PTEN [6].
  • Recent studies show that PTEN is associated with several brain diseases other than cancer, suggesting a broader role of PTEN in CNS pathophysiology [7].
  • Overall, our data indicate that T-ALL cells inactivate PTEN mostly in a nondeletional, posttranslational manner [8].
  • Inactivation of PTEN/p27(kip1) proteins is a specific feature in the progression of endometrial carcinoma in obese patients [9].
 

Psychiatry related information on PTEN

 

High impact information on PTEN

 

Chemical compound and disease context of PTEN

 

Biological context of PTEN

  • Certain structural features of PTEN contribute to its specificity for PIP3, as well as its role(s) in regulating cellular proliferation and apoptosis [1].
  • By specifically dephosphorylating the D3 position of PIP3, the PTEN tumor suppressor functions as a negative regulator of signaling processes downstream of this lipid second messenger [1].
  • However, mutations in MADH4 are only present in a subset of JP cases, and although mutations in the gene for phosphatase and tensin homolog (PTEN) have been described in a few families, undefined genetic heterogeneity remains [21].
  • PI(3)K-mediated activation of the cell survival kinase PKB/Akt, and negative regulation of PI(3)K signalling by the tumour suppressor PTEN (refs 3, 4) are key regulatory events in tumorigenesis [22].
  • PTEN is an important tumor suppressor gene [3].
 

Anatomical context of PTEN

 

Associations of PTEN with chemical compounds

  • The myotubularin-related genes define a large family of eukaryotic proteins, most of them initially characterized by the presence of a ten-amino acid consensus sequence related to the active sites of tyrosine phosphatases, dual-specificity protein phosphatases and the lipid phosphatase PTEN [27].
  • Tumor suppressor PTEN inhibits integrin- and growth factor-mediated mitogen-activated protein (MAP) kinase signaling pathways [16].
  • In addition, the effect of PTEN on p27(KIP1) and the cell cycle can be mimicked by treatment of U87MG cells with LY294002, a selective inhibitor of PI 3-kinase [28].
  • Furthermore, PTEN is a protein phosphatase, with the ability to dephosphorylate both serine and threonine residues [29].
  • Forced expression of PTEN in a PTEN-negative and doxorubicin-resistant ALL line (EU-1) resulted in decreased cell growth and enhanced sensitivity to doxorubicin [30].
  • Combining trastuzumab with inhibitors of the Akt/mTOR pathway is a clinically applicable strategy and combinations of trastuzumab with triciribine or RAD001 are promising regimens for rescue of trastuzumab resistance caused by PTEN loss [31].
  • Next, we further defined the underlying mechanisms responsible for the COOH-terminal tail region in modulating PTEN biological activity [32].
  • Of the 7 lines with disrupted PTEN function, only 1 tumor line (GBM10) was significantly sensitive to RAD001 therapy (25% prolongation in median survival), whereas 1 of 10 xenograft lines with wild-type PTEN was significantly sensitive to RAD001 (GS22; 34% prolongation in survival) [33].
 

Physical interactions of PTEN

 

Enzymatic interactions of PTEN

  • Expression of wild-type PTEN but not of mutant forms unable to dephosphorylate phosphoinositides reduced the expression of cyclin D1 [17].
  • The tumor suppressor PTEN dephosphorylates focal adhesion kinase (FAK) and inhibits integrin-mediated cell spreading and cell migration [16].
  • LKB1 interacts with and phosphorylates PTEN: a functional link between two proteins involved in cancer predisposing syndromes [39].
  • The tumor suppressor phosphatase and tensin homologue deleted from chromosome 10 (PTEN) gene is a negative regulator of the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt/PKB) signaling pathway [40].
  • PTEN expression induced decreased Sp1 DNA binding by dephosphorylating Sp1 and interfered with transcriptional transactivation of IGF-II by HBx in hepatoma cells [41].
 

Regulatory relationships of PTEN

  • PTEN induces cell cycle arrest by decreasing the level and nuclear localization of cyclin D1 [17].
  • These data indicate that BMP2 exposure can regulate PTEN protein levels by decreasing PTEN's association with the degradative pathway [42].
  • The purpose of this study was to determine whether PTEN controls VEGF expression in gliomas under normoxic conditions [43].
  • Furthermore, loss of PTEN can result in resistance to apoptosis by activating MDM2-mediated antiapoptotic mechanism [30].
  • On the other hand, androgens protected prostate cancer cells from PTEN-induced apoptosis in an AR-dependent manner [44].
  • Increased PTEN expression in unstimulated MCF-7 breast cancer cells results in a 51% increase in phosphatidic acid, with a decrease in phosphatidylcholine, suggesting that PTEN may regulate phospholipase D (PLD) [45].
 

Other interactions of PTEN

  • Mutations in TP53 and PTEN are mutually exclusive in either compartment [2].
  • Activation of PI3K pathway components occurs by PTEN loss and by AKT3 amplification [46].
  • Conversely, constitutive activation of PIK3CA results in resistance to p53-related apoptosis in PTEN deficient cells [47].
  • As lipid phosphatases, PTEN- and MTM1-related (MTMR) proteins dephosphorylate the products of phosphoinositide 3-kinases and antagonize downstream effectors that utilize 3-phosphoinositides as ligands for protein targeting domains or allosteric activation [48].
  • Mechanistically, PTEN increases the phosphorylation of beta-catenin and enhances its rate of degradation [26].
  • Our results support the notion that loss of PTEN function in human prostate cancer may specifically facilitate bone rather than other organ metastasis and suggest that Rac1, as a PTEN effector, may contribute to this metastatic tropism [49].
  • Overexpression of the NF-kappaB superrepressor increased PTEN expression and JNK activity, whereas overexpression of the p65 NF-kappaB subunit reduced both basal and NaBT-mediated JNK activation and PTEN expression [50].
 

Analytical, diagnostic and therapeutic context of PTEN

References

  1. PTEN and myotubularin: novel phosphoinositide phosphatases. Maehama, T., Taylor, G.S., Dixon, J.E. Annu. Rev. Biochem. (2001) [Pubmed]
  2. Frequent somatic mutations in PTEN and TP53 are mutually exclusive in the stroma of breast carcinomas. Kurose, K., Gilley, K., Matsumoto, S., Watson, P.H., Zhou, X.P., Eng, C. Nat. Genet. (2002) [Pubmed]
  3. The PTEN/PI3K pathway governs normal vascular development and tumor angiogenesis. Hamada, K., Sasaki, T., Koni, P.A., Natsui, M., Kishimoto, H., Sasaki, J., Yajima, N., Horie, Y., Hasegawa, G., Naito, M., Miyazaki, J., Suda, T., Itoh, H., Nakao, K., Mak, T.W., Nakano, T., Suzuki, A. Genes Dev. (2005) [Pubmed]
  4. Feedback inhibition of Akt signaling limits the growth of tumors lacking Tsc2. Manning, B.D., Logsdon, M.N., Lipovsky, A.I., Abbott, D., Kwiatkowski, D.J., Cantley, L.C. Genes Dev. (2005) [Pubmed]
  5. PTEN and TNF-alpha regulation of the intestinal-specific Cdx-2 homeobox gene through a PI3K, PKB/Akt, and NF-kappaB-dependent pathway. Kim, S., Domon-Dell, C., Wang, Q., Chung, D.H., Di Cristofano, A., Pandolfi, P.P., Freund, J.N., Evers, B.M. Gastroenterology (2002) [Pubmed]
  6. EF24 induces G2/M arrest and apoptosis in cisplatin-resistant human ovarian cancer cells by increasing PTEN expression. Selvendiran, K., Tong, L., Vishwanath, S., Bratasz, A., Trigg, N.J., Kutala, V.K., Hideg, K., Kuppusamy, P. J. Biol. Chem. (2007) [Pubmed]
  7. Phosphatase PTEN in neuronal injury and brain disorders. Chang, N., El-Hayek, Y.H., Gomez, E., Wan, Q. Trends Neurosci. (2007) [Pubmed]
  8. PTEN posttranslational inactivation and hyperactivation of the PI3K/Akt pathway sustain primary T cell leukemia viability. Silva, A., Yunes, J.A., Cardoso, B.A., Martins, L.R., Jotta, P.Y., Abecasis, M., Nowill, A.E., Leslie, N.R., Cardoso, A.A., Barata, J.T. J. Clin. Invest. (2008) [Pubmed]
  9. Combined PTEN and p27kip1 protein expression patterns are associated with obesity and prognosis in endometrial carcinomas. Dellas, A., Jundt, G., Sartorius, G., Schneider, M., Moch, H. Clin. Cancer Res. (2009) [Pubmed]
  10. The role of PTEN, a phosphatase gene, in inherited and sporadic nonmedullary thyroid tumors. Eng, C. Recent Prog. Horm. Res. (1999) [Pubmed]
  11. Expression of the PTEN tumour suppressor protein during human development. Gimm, O., Attié-Bitach, T., Lees, J.A., Vekemans, M., Eng, C. Hum. Mol. Genet. (2000) [Pubmed]
  12. Activation of Akt/PKB, increased phosphorylation of Akt substrates and loss and altered distribution of Akt and PTEN are features of Alzheimer's disease pathology. Griffin, R.J., Moloney, A., Kelliher, M., Johnston, J.A., Ravid, R., Dockery, P., O'Connor, R., O'Neill, C. J. Neurochem. (2005) [Pubmed]
  13. Tumor suppressor PTEN affects tau phosphorylation: deficiency in the phosphatase activity of PTEN increases aggregation of an FTDP-17 mutant Tau. Zhang, X., Zhang, Y.W., Liu, S., Bulloj, A., Tong, G.G., Zhang, Z., Liao, F.F., Xu, H. Molecular neurodegeneration [electronic resource]. (2006) [Pubmed]
  14. Pten and the Brain: Sizing up Social Interaction. Greer, J.M., Wynshaw-Boris, A. Neuron (2006) [Pubmed]
  15. Phosphoinositides Specify Polarity during Epithelial Organ Development. Comer, F.I., Parent, C.A. Cell (2007) [Pubmed]
  16. Tumor suppressor PTEN inhibits integrin- and growth factor-mediated mitogen-activated protein (MAP) kinase signaling pathways. Gu, J., Tamura, M., Yamada, K.M. J. Cell Biol. (1998) [Pubmed]
  17. PTEN induces cell cycle arrest by decreasing the level and nuclear localization of cyclin D1. Radu, A., Neubauer, V., Akagi, T., Hanafusa, H., Georgescu, M.M. Mol. Cell. Biol. (2003) [Pubmed]
  18. PTEN coordinates G(1) arrest by down-regulating cyclin D1 via its protein phosphatase activity and up-regulating p27 via its lipid phosphatase activity in a breast cancer model. Weng, L.P., Brown, J.L., Eng, C. Hum. Mol. Genet. (2001) [Pubmed]
  19. Antiapoptotic signaling in LNCaP prostate cancer cells: a survival signaling pathway independent of phosphatidylinositol 3'-kinase and Akt/protein kinase B. Carson, J.P., Kulik, G., Weber, M.J. Cancer Res. (1999) [Pubmed]
  20. Role of the phosphatidylinositol 3'-kinase/PTEN/Akt kinase pathway in the overexpression of fatty acid synthase in LNCaP prostate cancer cells. Van de Sande, T., De Schrijver, E., Heyns, W., Verhoeven, G., Swinnen, J.V. Cancer Res. (2002) [Pubmed]
  21. Germline mutations of the gene encoding bone morphogenetic protein receptor 1A in juvenile polyposis. Howe, J.R., Bair, J.L., Sayed, M.G., Anderson, M.E., Mitros, F.A., Petersen, G.M., Velculescu, V.E., Traverso, G., Vogelstein, B. Nat. Genet. (2001) [Pubmed]
  22. Colorectal carcinomas in mice lacking the catalytic subunit of PI(3)Kgamma. Sasaki, T., Irie-Sasaki, J., Horie, Y., Bachmaier, K., Fata, J.E., Li, M., Suzuki, A., Bouchard, D., Ho, A., Redston, M., Gallinger, S., Khokha, R., Mak, T.W., Hawkins, P.T., Stephens, L., Scherer, S.W., Tsao, M., Penninger, J.M. Nature (2000) [Pubmed]
  23. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Manning, B.D., Tee, A.R., Logsdon, M.N., Blenis, J., Cantley, L.C. Mol. Cell (2002) [Pubmed]
  24. Induction of intrahepatic cholangiocellular carcinoma by liver-specific disruption of Smad4 and Pten in mice. Xu, X., Kobayashi, S., Qiao, W., Li, C., Xiao, C., Radaeva, S., Stiles, B., Wang, R.H., Ohara, N., Yoshino, T., LeRoith, D., Torbenson, M.S., Gores, G.J., Wu, H., Gao, B., Deng, C.X. J. Clin. Invest. (2006) [Pubmed]
  25. Akt2, phosphatidylinositol 3-kinase, and PTEN are in lipid rafts of intestinal cells: role in absorption and differentiation. Li, X., Leu, S., Cheong, A., Zhang, H., Baibakov, B., Shih, C., Birnbaum, M.J., Donowitz, M. Gastroenterology (2004) [Pubmed]
  26. Tumor suppressor PTEN inhibits nuclear accumulation of beta-catenin and T cell/lymphoid enhancer factor 1-mediated transcriptional activation. Persad, S., Troussard, A.A., McPhee, T.R., Mulholland, D.J., Dedhar, S. J. Cell Biol. (2001) [Pubmed]
  27. The myotubularin family: from genetic disease to phosphoinositide metabolism. Laporte, J., Blondeau, F., Buj-Bello, A., Mandel, J.L. Trends Genet. (2001) [Pubmed]
  28. PTEN/MMAC1/TEP1 suppresses the tumorigenicity and induces G1 cell cycle arrest in human glioblastoma cells. Li, D.M., Sun, H. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  29. Protean PTEN: form and function. Waite, K.A., Eng, C. Am. J. Hum. Genet. (2002) [Pubmed]
  30. PTEN reverses MDM2-mediated chemotherapy resistance by interacting with p53 in acute lymphoblastic leukemia cells. Zhou, M., Gu, L., Findley, H.W., Jiang, R., Woods, W.G. Cancer Res. (2003) [Pubmed]
  31. Preclinical testing of clinically applicable strategies for overcoming trastuzumab resistance caused by PTEN deficiency. Lu, C.H., Wyszomierski, S.L., Tseng, L.M., Sun, M.H., Lan, K.H., Neal, C.L., Mills, G.B., Hortobagyi, G.N., Esteva, F.J., Yu, D. Clin. Cancer Res. (2007) [Pubmed]
  32. Regulation of PTEN activity by its carboxyl-terminal autoinhibitory domain. Odriozola, L., Singh, G., Hoang, T., Chan, A.M. J. Biol. Chem. (2007) [Pubmed]
  33. PTEN loss does not predict for response to RAD001 (Everolimus) in a glioblastoma orthotopic xenograft test panel. Yang, L., Clarke, M.J., Carlson, B.L., Mladek, A.C., Schroeder, M.A., Decker, P., Wu, W., Kitange, G.J., Grogan, P.T., Goble, J.M., Uhm, J., Galanis, E., Giannini, C., Lane, H.A., James, C.D., Sarkaria, J.N. Clin. Cancer Res. (2008) [Pubmed]
  34. Activation of p53-Dependent Growth Suppression in Human Cells by Mutations in PTEN or PIK3CA. Kim, J.S., Lee, C., Bonifant, C.L., Ressom, H., Waldman, T. Mol. Cell. Biol. (2007) [Pubmed]
  35. PTEN interactions with focal adhesion kinase and suppression of the extracellular matrix-dependent phosphatidylinositol 3-kinase/Akt cell survival pathway. Tamura, M., Gu, J., Danen, E.H., Takino, T., Miyamoto, S., Yamada, K.M. J. Biol. Chem. (1999) [Pubmed]
  36. TGFbeta-induced downregulation of E-cadherin-based cell-cell adhesion depends on PI3-kinase and PTEN. Vogelmann, R., Nguyen-Tat, M.D., Giehl, K., Adler, G., Wedlich, D., Menke, A. J. Cell. Sci. (2005) [Pubmed]
  37. Phosphorylation of the PTEN tail acts as an inhibitory switch by preventing its recruitment into a protein complex. Vazquez, F., Grossman, S.R., Takahashi, Y., Rokas, M.V., Nakamura, N., Sellers, W.R. J. Biol. Chem. (2001) [Pubmed]
  38. Nuclear localization of PTEN is regulated by Ca(2+) through a tyrosil phosphorylation-independent conformational modification in major vault protein. Minaguchi, T., Waite, K.A., Eng, C. Cancer Res. (2006) [Pubmed]
  39. LKB1 interacts with and phosphorylates PTEN: a functional link between two proteins involved in cancer predisposing syndromes. Mehenni, H., Lin-Marq, N., Buchet-Poyau, K., Reymond, A., Collart, M.A., Picard, D., Antonarakis, S.E. Hum. Mol. Genet. (2005) [Pubmed]
  40. Adenovirus-mediated PTEN treatment combined with caffeine produces a synergistic therapeutic effect in colorectal cancer cells. Saito, Y., Gopalan, B., Mhashilkar, A.M., Roth, J.A., Chada, S., Zumstein, L., Ramesh, R. Cancer Gene Ther. (2003) [Pubmed]
  41. PTEN modulates insulin-like growth factor II (IGF-II)-mediated signaling; the protein phosphatase activity of PTEN downregulates IGF-II expression in hepatoma cells. Kang-Park, S., Lee, Y.I., Lee, Y.I. FEBS Lett. (2003) [Pubmed]
  42. BMP2 exposure results in decreased PTEN protein degradation and increased PTEN levels. Waite, K.A., Eng, C. Hum. Mol. Genet. (2003) [Pubmed]
  43. Mechanisms underlying PTEN regulation of vascular endothelial growth factor and angiogenesis. Gomez-Manzano, C., Fueyo, J., Jiang, H., Glass, T.L., Lee, H.Y., Hu, M., Liu, J.L., Jasti, S.L., Liu, T.J., Conrad, C.A., Yung, W.K. Ann. Neurol. (2003) [Pubmed]
  44. Antagonism between PTEN/MMAC1/TEP-1 and androgen receptor in growth and apoptosis of prostatic cancer cells. Li, P., Nicosia, S.V., Bai, W. J. Biol. Chem. (2001) [Pubmed]
  45. PTEN regulates phospholipase D and phospholipase C. Alvarez-Breckenridge, C.A., Waite, K.A., Eng, C. Hum. Mol. Genet. (2007) [Pubmed]
  46. Use of human tissue to assess the oncogenic activity of melanoma-associated mutations. Chudnovsky, Y., Adams, A.E., Robbins, P.B., Lin, Q., Khavari, P.A. Nat. Genet. (2005) [Pubmed]
  47. p53 regulates cell survival by inhibiting PIK3CA in squamous cell carcinomas. Singh, B., Reddy, P.G., Goberdhan, A., Walsh, C., Dao, S., Ngai, I., Chou, T.C., O-Charoenrat, P., Levine, A.J., Rao, P.H., Stoffel, A. Genes Dev. (2002) [Pubmed]
  48. PTEN and myotubularin phosphatases: from 3-phosphoinositide dephosphorylation to disease. Wishart, M.J., Dixon, J.E. Trends Cell Biol. (2002) [Pubmed]
  49. The role of PTEN in prostate cancer cell tropism to the bone micro-environment. Wu, Z., McRoberts, K.S., Theodorescu, D. Carcinogenesis (2007) [Pubmed]
  50. Regulation of PTEN expression in intestinal epithelial cells by c-Jun NH2-terminal kinase activation and nuclear factor-kappaB inhibition. Wang, Q., Zhou, Y., Wang, X., Chung, D.H., Evers, B.M. Cancer Res. (2007) [Pubmed]
  51. mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Majumder, P.K., Febbo, P.G., Bikoff, R., Berger, R., Xue, Q., McMahon, L.M., Manola, J., Brugarolas, J., McDonnell, T.J., Golub, T.R., Loda, M., Lane, H.A., Sellers, W.R. Nat. Med. (2004) [Pubmed]
  52. PTEN represses RNA Polymerase I transcription by disrupting the SL1 complex. Zhang, C., Comai, L., Johnson, D.L. Mol. Cell. Biol. (2005) [Pubmed]
  53. Growth and gene expression profile analyses of endometrial cancer cells expressing exogenous PTEN. Matsushima-Nishiu, M., Unoki, M., Ono, K., Tsunoda, T., Minaguchi, T., Kuramoto, H., Nishida, M., Satoh, T., Tanaka, T., Nakamura, Y. Cancer Res. (2001) [Pubmed]
 
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