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Phosphatase and tensin homolog (mutated in multiple advanced cancers 1)

Crystallographic structure of human PTEN. The N-terminal phosphatase domain is colored blue while the C-terminal C2 domain is colored red.[1]
Available structures
1d5r
Identifiers
Symbols PTEN; BZS; MGC11227; MHAM; MMAC1; PTEN1; TEP1
External IDs OMIM601728 MGI109583 HomoloGene265 GeneCards: PTEN Gene
EC number 3.1.3.67
Orthologs
Species Human Mouse
Entrez 5728 19211
Ensembl ENSG00000171862 ENSMUSG00000013663
UniProt P60484 Q3UFB0
RefSeq (mRNA) NM_000314 NM_008960
RefSeq (protein) NP_000305 NP_032986
Location (UCSC) Chr 10:
89.61 - 89.72 Mb
Chr 19:
32.82 - 32.89 Mb
PubMed search [1] [2]
Space-filling model of the PTEN protein (blue) complexed with tartaric acid (brown).[1]

In molecular biology, phosphatase and tensin homolog (PTEN) is a protein which in humans is encoded by the PTEN gene.[2] Mutations of this gene are a step in the development of many cancers.

PTEN acts as a tumor suppressor gene through the action of its phosphatase protein product. This phosphatase is involved in the regulation of the cell cycle, preventing cells from growing and dividing too rapidly.[3]

This gene was identified as a tumor suppressor that is mutated in a large number of cancers at high frequency. The protein encoded by this gene is a phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase. It contains a tensin like domain as well as a catalytic domain similar to that of the dual specificity protein tyrosine phosphatases. Unlike most of the protein tyrosine phosphatases, this protein preferentially dephosphorylates phosphoinositide substrates. It negatively regulates intracellular levels of phosphatidylinositol-3,4,5-trisphosphate in cells and functions as a tumor suppressor by negatively regulating Akt/PKB signaling pathway.[4]

Contents

Function and structure

The corresponding PTEN protein is found in almost all tissues in the body. PTEN protein acts as a phosphatase to dephosphorylate phosphatidylinositol (3,4,5)-trisphosphate (PtdIns (3,4,5)P3 or PIP3). PTEN specifically catalyses the dephosporylation of the 3` phosphate of the inositol ring in PIP3, resulting in the biphosphate product PIP2 (PtdIns(4,5)P2). This dephosphorylation is important because it results in inhibition of the AKT signaling pathway.

The structure of PTEN (solved by X-ray crystallography, see figure to the upper right[1]) reveals that it consists of a phosphatase domain, and a C2 domain: the phosphatase domain contains the active site which carries out the enzymatic function of the protein, whilst the C2 domain binds the phospholipid membrane. Thus PTEN binds the membrane through its C2 domain bringing the active site to the membrane-bound PIP3 to de-phosphorylate it.

When the PTEN enzyme is functioning properly, it acts as part of a chemical pathway that signals cells to stop dividing and causes cells to undergo programmed cell death (apoptosis) when necessary. These functions prevent uncontrolled cell growth that can lead to the formation of tumors. There is also evidence that the protein made by the PTEN gene may play a role in cell movement (migration) and sticking (adhesion) of cells to surrounding tissues.

PTEN orthologs [5] have been identified in most mammals for which complete genome data are available.

Clinical significance

PTEN is one of the most commonly lost tumor suppressors in human cancer. During tumor development, mutations and deletions of PTEN occur that inactivate its enzymatic activity leading to increased cell proliferation and reduced cell death. Frequent genetic inactivation of PTEN occurs in glioblastoma, endometrial cancer, prostate cancer, and reduced expression is found in many other tumor types such as lung and breast cancer.

PTEN mutation also causes a variety of inherited predispositions to cancer.

In-vitro studies of olaparib show potential for treatment of PTEN mutant cancers.[6]

Cowden syndrome: Researchers have found more than 70 mutations in the PTEN gene in people with Cowden syndrome. These mutations can be changes in a small number of base pairs or, in some cases, deletions of a large number of base pairs. Most of these mutations cause the PTEN gene to make a protein that does not function properly or does not work at all. The defective protein is unable to stop cell division or signal abnormal cells to die, which can lead to tumor growth, particularly in the breast, thyroid or uterus.

Other disorders: Mutations in the PTEN gene cause several other disorders that, like Cowden syndrome, are characterized by the development of noncancerous tumors called hamartomas. These disorders include Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome, and Proteus-like syndrome. Together, the disorders caused by PTEN mutations are called PTEN hamartoma tumor syndromes, or PHTS. Mutations responsible for these syndromes cause the resulting protein to be nonfunctional or absent. The defective protein allows the cell to divide in an uncontrolled way and prevents damaged cells from dying, which can lead to the growth of tumors.

Cell lines

Cell lines with known PTEN mutations include:[citation needed]

  • prostate: LNCaP, PC-3
  • kidney: 786-O
  • glioblastoma: U87MG

Interactions

PTEN (gene) has been shown to interact with CSNK2A2,[7] Casein kinase 2, alpha 1,[7] PTK2,[8][9] Major vault protein,[10] Androgen receptor,[11] P53,[12] MAGI3[13] and NEDD4.[14]

See also

References

  1. ^ a b c PDB 1d5r; Lee JO, Yang H, Georgescu MM, Di Cristofano A, Maehama T, Shi Y, Dixon JE, Pandolfi P, Pavletich NP (October 1999). "Crystal structure of the PTEN tumor suppressor: implications for its phosphoinositide phosphatase activity and membrane association". Cell 99 (3): 323–34. doi:10.1016/S0092-8674(00)81663-3. PMID 10555148. 
  2. ^ Steck PA, Pershouse MA, Jasser SA, Yung WK, Lin H, Ligon AH, Langford LA, Baumgard ML, Hattier T, Davis T, Frye C, Hu R, Swedlund B, Teng DH, Tavtigian SV (April 1997). "Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers". Nat. Genet. 15 (4): 356–62. doi:10.1038/ng0497-356. PMID 9090379. 
  3. ^ Chu EC, Tarnawski AS (October 2004). "PTEN regulatory functions in tumor suppression and cell biology". Med. Sci. Monit. 10 (10): RA235–41. PMID 15448614. http://www.medscimonit.com/fulltxt.php?ICID=11797. 
  4. ^ "Entrez Gene: PTEN phosphatase and tensin homolog (mutated in multiple advanced cancers 1)". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5728. 
  5. ^ "OrthoMaM phylogenetic marker: PTEN coding sequence". http://www.orthomam.univ-montp2.fr/orthomam/data/cds/detailMarkers/ENSG00000171862_PTEN.xml. 
  6. ^ EMBO Molecular Medicine. Sept 2009
  7. ^ a b Miller, Susan J; Lou David Y, Seldin David C, Lane William S, Neel Benjamin G (Sep. 2002). "Direct identification of PTEN phosphorylation sites". FEBS Lett. (Netherlands) 528 (1-3): 145–53. ISSN 0014-5793. PMID 12297295. 
  8. ^ Tamura, M; Gu J, Danen E H, Takino T, Miyamoto S, Yamada K M (Jul. 1999). "PTEN interactions with focal adhesion kinase and suppression of the extracellular matrix-dependent phosphatidylinositol 3-kinase/Akt cell survival pathway". J. Biol. Chem. (UNITED STATES) 274 (29): 20693–703. ISSN 0021-9258. PMID 10400703. 
  9. ^ Haier, Jörg; Nicolson Garth L (Feb. 2002). "PTEN regulates tumor cell adhesion of colon carcinoma cells under dynamic conditions of fluid flow". Oncogene (England) 21 (9): 1450–60. doi:10.1038/sj.onc.1205213. ISSN 0950-9232. PMID 11857088. 
  10. ^ Yu, Zhenbao; Fotouhi-Ardakani Nasser, Wu Liangtang, Maoui Meryem, Wang Shenglong, Banville Denis, Shen Shi-Hsiang (Oct. 2002). "PTEN associates with the vault particles in HeLa cells". J. Biol. Chem. (United States) 277 (43): 40247–52. doi:10.1074/jbc.M207608200. ISSN 0021-9258. PMID 12177006. 
  11. ^ Lin, Hui-Kuan; Hu Yueh-Chiang, Lee Dong Kun, Chang Chawnshang (Oct. 2004). "Regulation of androgen receptor signaling by PTEN (phosphatase and tensin homolog deleted on chromosome 10) tumor suppressor through distinct mechanisms in prostate cancer cells". Mol. Endocrinol. (United States) 18 (10): 2409–23. doi:10.1210/me.2004-0117. ISSN 0888-8809. PMID 15205473. 
  12. ^ Freeman, Daniel J; Li Andrew G, Wei Gang, Li Heng-Hong, Kertesz Nathalie, Lesche Ralf, Whale Andrew D, Martinez-Diaz Hilda, Rozengurt Nora, Cardiff Robert D, Liu Xuan, Wu Hong (Feb. 2003). "PTEN tumor suppressor regulates p53 protein levels and activity through phosphatase-dependent and -independent mechanisms". Cancer Cell (United States) 3 (2): 117–30. ISSN 1535-6108. PMID 12620402. 
  13. ^ Wu, Y; Dowbenko D, Spencer S, Laura R, Lee J, Gu Q, Lasky L A (Jul. 2000). "Interaction of the tumor suppressor PTEN/MMAC with a PDZ domain of MAGI3, a novel membrane-associated guanylate kinase". J. Biol. Chem. (UNITED STATES) 275 (28): 21477–85. doi:10.1074/jbc.M909741199. ISSN 0021-9258. PMID 10748157. 
  14. ^ Wang, Xinjiang; Shi Yuji, Wang Junru, Huang Guochang, Jiang Xuejun (Sep. 2008). "Crucial role of the C-terminus of PTEN in antagonizing NEDD4-1-mediated PTEN ubiquitination and degradation". Biochem. J. (England) 414 (2): 221–9. doi:10.1042/BJ20080674. PMID 18498243. 

Further reading

  • Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner SH, Giovanella BC, Ittmann M, Tycko B, Hibshoosh H, Wigler MH, Parsons R (1997). "PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer.". Science 275 (5308): 1943–1947. doi:10.1126/science.275.5308.1943. PMID 9072974. 
  • Simpson L, Parsons R (2001). "PTEN: life as a tumor suppressor". Exp Cell Res 264 (1): 29–41. doi:10.1006/excr.2000.5130. PMID 11237521. 
  • Chu EC, Tarnawski AS (2004). "PTEN regulatory functions in tumor suppression and cell biology". Med Sci Monit 10 (10): RA235–41. PMID 15448614. 
  • Eng C (2003). "PTEN: one gene, many syndromes". Hum Mutat 22 (3): 183–98. doi:10.1002/humu.10257. PMID 12938083. 
  • Hamada K, Sasaki T, Koni PA, Natsui M, Kishimoto H, Sasaki J, Yajima N, Horie Y, Hasegawa G, Naito M, Miyazaki J, Suda T, Itoh H, Nakao K, Mak TW, Nakano T, Suzuki A (2005). "The PTEN/PI3K pathway governs normal vascular development and tumor angiogenesis". Genes Dev 19 (17): 2054–65. doi:10.1101/gad.1308805. PMID 16107612. 
  • Leslie NR, Downes CP (2004). "PTEN function: how normal cells control it and tumour cells lose it". Biochem J 382 (Pt 1): 1–11. doi:10.1042/BJ20040825. PMID 15193142. 
  • Pilarski R, Eng C (2004). "Will the real Cowden syndrome please stand up (again)? Expanding mutational and clinical spectra of the PTEN hamartoma tumour syndrome". J Med Genet 41 (5): 323–6. doi:10.1136/jmg.2004.018036. PMID 15121767. 
  • Sansal I, Sellers WR (2004). "The biology and clinical relevance of the PTEN tumor suppressor pathway". J Clin Oncol 22 (14): 2954–63. doi:10.1200/JCO.2004.02.141. PMID 15254063. 
  • Waite KA, Eng C (2002). "Protean PTEN: form and function". Am J Hum Genet 70 (4): 829–44. doi:10.1086/340026. PMID 11875759. 
  • Zhou XP, Waite KA, Pilarski R, Hampel H, Fernandez MJ, Bos C, Dasouki M, Feldman GL, Greenberg LA, Ivanovich J, Matloff E, Patterson A, Pierpont ME, Russo D, Nassif NT, Eng C (2003). "Germline PTEN promoter mutations and deletions in Cowden/Bannayan-Riley-Ruvalcaba syndrome result in aberrant PTEN protein and dysregulation of the phosphoinositol-3-kinase/Akt pathway". Am J Hum Genet 73 (2): 404–11. doi:10.1086/377109. PMID 12844284. 
  • Ji S-P, Zhang Y, Cleemput JV, Jiang W, Liao M, Li L, Wan Q, Backstrom JR, Zhang X (2006). "Disruption of PTEN coupling with 5-HT2C receptors suppresses behavioral responses induced by drugs of abuse". Nature Medicine 12 (3): 324–9. doi:10.1038/nm1349. PMID 16474401. 

External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.








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