PTEN (gene)

Phosphatase and tensin homolog

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
PDB Ortholog search: PDBe, RCSB
Identifiers
SymbolsPTEN ; 10q23del; BZS; CWS1; DEC; GLM2; MHAM; MMAC1; PTEN1; TEP1
External IDsOMIM: 601728 HomoloGene: 265 IUPHAR: 2497 GeneCards: PTEN Gene
EC number3.1.3.16, 3.1.3.48, 3.1.3.67
Orthologs
SpeciesHumanMouse
Entrez572819211
EnsemblENSG00000171862ENSMUSG00000013663
UniProtP60484O08586
RefSeq (mRNA)NM_000314NM_008960
RefSeq (protein)NP_000305NP_032986
Location (UCSC)Chr 10:
89.62 – 89.73 Mb		Chr 19:
32.76 – 32.83 Mb
PubMed search
Space-filling model of the PTEN protein (blue) complexed with tartaric acid (brown).[1]

Phosphatase and tensin homolog (PTEN) is a protein that, in humans, is encoded by the PTEN gene.[2] Mutations of this gene are a step in the development of many cancers. PTEN orthologs[3] have been identified in most mammals for which complete genome data are available.

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]

Function

The PTEN protein widely expressed through out 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.

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.[5] It is one of the targets for drug candidates such as the oncomiR, MIRN21.

Structure

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, while 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.


The two domains of PTEN, a protein tyrosine phosphatase domain and a C2 domain, are inherited together as a single unit and thus constitute a superdomain, not only in PTEN but also in various other proteins in fungi, plants and animals, for example, tensin proteins and auxilin.[6]

Clinical significance

Cancer

PTEN is one of the most commonly lost tumor suppressors in human cancer; in fact, up to 70% of men with prostate cancer are estimated to have lost a copy of the PTEN gene at the time of diagnosis.[7]

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, and prostate cancer; and reduced expression is found in many other tumor types such as lung and breast cancer. Furthermore, PTEN mutation also causes a variety of inherited predispositions to cancer.

Non-cancerous neoplasia

Researchers have identified 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.[8]

Mutations in the PTEN gene cause several other disorders that, like Cowden syndrome, are characterized by the development of non-cancerous tumors called hamartomas. These disorders include Bannayan-Riley-Ruvalcaba 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 non-functional 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.[8]

Brain function and autism

Defects of the PTEN gene have been cited to be a potential cause of autism spectrum disorders.[9] When defective, PTEN protein interacts with the protein of a second gene known as Tp53 to dampen energy production in neurons. This severe stress leads to a spike in harmful mitochondrial DNA changes and abnormal levels of energy production in the cerebellum and hippocampus, brain regions critical for social behavior and cognition. When PTEN protein is insufficient, its interaction with p53 triggers deficiencies and defects in other proteins that also have been found in patients with learning disabilities including autism.[9]

Patients with defective PTEN can develop cerebellar mass lesions called dysplastic gangliocytomas or Lhermitte–Duclos disease.[8]

Cell regeneration

PTEN's strong link to cell growth inhibition is being studied as a possible therapeutic target in tissues that do not traditionally regenerate in mature animals, such as central neurons. PTEN deletion mutants have recently[10] been shown to allow nerve regeneration in mice.[11]

Cell lines

Cell lines with known PTEN mutations include:

Interactions

PTEN (gene) has been shown to interact with:

See also

References

  1. ↑ 1.0 1.1 1.2 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 et al. (Apr 1997). "Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers". Nature Genetics 15 (4): 356–62. doi:10.1038/ng0497-356. PMID 9090379.
  3. ↑ "OrthoMaM phylogenetic marker: PTEN coding sequence".
  4. ↑ "Entrez Gene: PTEN phosphatase and tensin homolog (mutated in multiple advanced cancers 1)".
  5. ↑ Chu EC, Tarnawski AS (Oct 2004). "PTEN regulatory functions in tumor suppression and cell biology". Medical Science Monitor 10 (10): RA235–41. PMID 15448614.
  6. ↑ Haynie DT, Xue B (Feb 2015). "Superdomains in the protein structure hierarchy: The case of PTP-C2". Protein Science. doi:10.1002/pro.2664. PMID 25694109.
  7. ↑ Chen Z, Trotman LC, Shaffer D, Lin HK, Dotan ZA, Niki M et al. (Aug 2005). "Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis". Nature 436 (7051): 725–30. doi:10.1038/nature03918. PMC 1939938. PMID 16079851.
  8. ↑ 8.0 8.1 8.2 Pilarski R, Eng C (May 2004). "Will the real Cowden syndrome please stand up (again)? Expanding mutational and clinical spectra of the PTEN hamartoma tumour syndrome". Journal of Medical Genetics 41 (5): 323–6. doi:10.1136/jmg.2004.018036. PMC 1735782. PMID 15121767.
  9. ↑ 9.0 9.1 Napoli E, Ross-Inta C, Wong S, Hung C, Fujisawa Y, Sakaguchi D et al. (2012). Bai Y, ed. "Mitochondrial dysfunction in Pten haplo-insufficient mice with social deficits and repetitive behavior: interplay between Pten and p53". PloS One 7 (8): e42504. doi:10.1371/journal.pone.0042504. PMC 3416855. PMID 22900024.
  10. ↑ "Rodent of the Week: Nerves regenerated after spinal cord injury". The Los Angeles Times. August 13, 2010.
  11. ↑ Liu K, Lu Y, Lee JK, Samara R, Willenberg R, Sears-Kraxberger I et al. (Sep 2010). "PTEN deletion enhances the regenerative ability of adult corticospinal neurons". Nature Neuroscience 13 (9): 1075–81. doi:10.1038/nn.2603. PMC 2928871. PMID 20694004.
  12. ↑ 12.0 12.1 Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI et al. (Mar 1997). "PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer". Science 275 (5308): 1943–7. doi:10.1126/science.275.5308.1943. PMID 9072974.
  13. ↑ 13.0 13.1 Miller SJ, Lou DY, Seldin DC, Lane WS, Neel BG (Sep 2002). "Direct identification of PTEN phosphorylation sites". FEBS Letters 528 (1-3): 145–53. doi:10.1016/S0014-5793(02)03274-X. PMID 12297295.
  14. ↑ Wu Y, Dowbenko D, Spencer S, Laura R, Lee J, Gu Q et al. (Jul 2000). "Interaction of the tumor suppressor PTEN/MMAC with a PDZ domain of MAGI3, a novel membrane-associated guanylate kinase". The Journal of Biological Chemistry 275 (28): 21477–85. doi:10.1074/jbc.M909741199. PMID 10748157.
  15. ↑ Yu Z, Fotouhi-Ardakani N, Wu L, Maoui M, Wang S, Banville D et al. (Oct 2002). "PTEN associates with the vault particles in HeLa cells". The Journal of Biological Chemistry 277 (43): 40247–52. doi:10.1074/jbc.M207608200. PMID 12177006.
  16. ↑ Wang X, Shi Y, Wang J, Huang G, Jiang X (Sep 2008). "Crucial role of the C-terminus of PTEN in antagonizing NEDD4-1-mediated PTEN ubiquitination and degradation". The Biochemical Journal 414 (2): 221–9. doi:10.1042/BJ20080674. PMID 18498243.
  17. ↑ Lin HK, Hu YC, Lee DK, Chang C (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". Molecular Endocrinology 18 (10): 2409–23. doi:10.1210/me.2004-0117. PMID 15205473.
  18. ↑ Freeman DJ, Li AG, Wei G, Li HH, Kertesz N, Lesche R et al. (Feb 2003). "PTEN tumor suppressor regulates p53 protein levels and activity through phosphatase-dependent and -independent mechanisms". Cancer Cell 3 (2): 117–30. doi:10.1016/S1535-6108(03)00021-7. PMID 12620407.
  19. ↑ Tamura M, Gu J, Danen EH, Takino T, Miyamoto S, Yamada KM (Jul 1999). "PTEN interactions with focal adhesion kinase and suppression of the extracellular matrix-dependent phosphatidylinositol 3-kinase/Akt cell survival pathway". The Journal of Biological Chemistry 274 (29): 20693–703. doi:10.1074/jbc.274.29.20693. PMID 10400703.
  20. ↑ Haier J, Nicolson GL (Feb 2002). "PTEN regulates tumor cell adhesion of colon carcinoma cells under dynamic conditions of fluid flow". Oncogene 21 (9): 1450–60. doi:10.1038/sj.onc.1205213. PMID 11857088.

Further reading

External links

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