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{{Infobox_gene}}
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[[File:PTEN.png|right|thumbnail|270px|[[Space-filling model]] of the PTEN protein (blue) complexed with [[tartaric acid]] (brown).<ref name="pmid10555148"/>]]
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<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
'''Phosphatase and tensin homolog''' ('''PTEN''') is a [[protein]] that, in humans, is encoded by the ''PTEN'' [[gene]].<ref name="pmid9090379">{{cite journal | vauthors = 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 | title = Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers | journal = Nature Genetics | volume = 15 | issue = 4 | pages = 356–62 | date = April 1997 | pmid = 9090379 | doi = 10.1038/ng0497-356 }}</ref>  Mutations of this gene are a step in the development of many [[cancer]]s. Genes corresponding to PTEN ([[orthologs]])<ref name="OrthoMaM">{{Cite web| title = OrthoMaM phylogenetic marker: PTEN coding sequence | url = http://www.orthomam.univ-montp2.fr/orthomam/data/cds/detailMarkers/ENSG00000171862_PTEN.xml }}</ref> have been identified in most [[mammals]] for which complete genome data are available.
{{GNF_Protein_box
| image = Pten.jpg
| image_source = PTEN structure (PDB entry 1D5R visualized using PyMOL)
| PDB =
| Name = Phosphatase and tensin homolog (mutated in multiple advanced cancers 1)
| HGNCid = 9588
| Symbol = PTEN
| AltSymbols =; BZS; MGC11227; MHAM; MMAC1; PTEN1; TEP1
| OMIM = 601728
| ECnumber = 
| Homologene = 265
| MGIid = 109583
<!-- The Following entry is a time stamp of the last bot update. It is typically hidden data -->
| DateOfBotUpdate = 18:42, 21 October 2007 (UTC)
| Function = {{GNF_GO|id=GO:0004438 |text = phosphatidylinositol-3-phosphatase activity}} {{GNF_GO|id=GO:0004722 |text = protein serine/threonine phosphatase activity}} {{GNF_GO|id=GO:0004725 |text = protein tyrosine phosphatase activity}} {{GNF_GO|id=GO:0005515 |text = protein binding}} {{GNF_GO|id=GO:0008138 |text = protein tyrosine/serine/threonine phosphatase activity}} {{GNF_GO|id=GO:0008289 |text = lipid binding}} {{GNF_GO|id=GO:0016314 |text = phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase activity}} {{GNF_GO|id=GO:0016787 |text = hydrolase activity}} {{GNF_GO|id=GO:0030165 |text = PDZ domain binding}} {{GNF_GO|id=GO:0051717 |text = inositol-1,3,4,5-tetrakisphosphate 3-phosphatase activity}} {{GNF_GO|id=GO:0051800 |text = phosphatidylinositol-3,4-bisphosphate 3-phosphatase activity}}
| Component = {{GNF_GO|id=GO:0005737 |text = cytoplasm}}
| Process = {{GNF_GO|id=GO:0000079 |text = regulation of cyclin-dependent protein kinase activity}} {{GNF_GO|id=GO:0006470 |text = protein amino acid dephosphorylation}} {{GNF_GO|id=GO:0006629 |text = lipid metabolic process}} {{GNF_GO|id=GO:0006917 |text = induction of apoptosis}} {{GNF_GO|id=GO:0007049 |text = cell cycle}} {{GNF_GO|id=GO:0007417 |text = central nervous system development}} {{GNF_GO|id=GO:0007507 |text = heart development}} {{GNF_GO|id=GO:0008283 |text = cell proliferation}} {{GNF_GO|id=GO:0008285 |text = negative regulation of cell proliferation}} {{GNF_GO|id=GO:0016477 |text = cell migration}} {{GNF_GO|id=GO:0030336 |text = negative regulation of cell migration}} {{GNF_GO|id=GO:0031647 |text = regulation of protein stability}} {{GNF_GO|id=GO:0043066 |text = negative regulation of apoptosis}} {{GNF_GO|id=GO:0045786 |text = negative regulation of progression through cell cycle}} {{GNF_GO|id=GO:0046855 |text = inositol phosphate dephosphorylation}} {{GNF_GO|id=GO:0046856 |text = phosphoinositide dephosphorylation}} {{GNF_GO|id=GO:0051895 |text = negative regulation of focal adhesion formation}} {{GNF_GO|id=GO:0051898 |text = negative regulation of protein kinase B signaling cascade}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 5728
    | Hs_Ensembl = 
    | Hs_RefseqProtein = NP_000305
    | Hs_RefseqmRNA = NM_000314
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 
    | Hs_GenLoc_start = 
    | Hs_GenLoc_end = 
    | Hs_Uniprot = 
    | Mm_EntrezGene = 19211
    | Mm_Ensembl = ENSMUSG00000013663
    | Mm_RefseqmRNA = NM_008960
    | Mm_RefseqProtein = NP_032986
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 19
    | Mm_GenLoc_start = 32823574
    | Mm_GenLoc_end = 32892157
    | Mm_Uniprot = Q3UFB0
  }}
}}
{{SI}}


''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.<ref name="pmid15448614"/> It is a target of many cancer drugs.


==Overview==
The protein encoded by this gene is a [[phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase]]. It contains a [[TNS1|tensin]]-like domain as well as a catalytic domain similar to that of the dual specificity [[protein tyrosine phosphatase]]s. Unlike most of the protein tyrosine phosphatases, this protein preferentially dephosphorylates [[phosphoinositide]] substrates. It negatively regulates intracellular levels of [[phosphatidylinositol (3,4,5)-trisphosphate|phosphatidylinositol-3,4,5-trisphosphate]] in cells and functions as a tumor suppressor by negatively regulating [[Akt/PKB signaling pathway]].<ref>{{Cite web| title = Entrez Gene: PTEN phosphatase and tensin homolog (mutated in multiple advanced cancers 1)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5728| accessdate = }}</ref>
'''PTEN''' ('''Phosphatase and Tensin homolog''') '''gene''' is a [[human]] [[gene]] that acts as a [[tumor suppressor gene]], which means that the [[protein]] encoded by this gene helps regulate the cycle of [[cell division]] by keeping cells from growing and dividing too rapidly or in an uncontrolled way. Mutations of this gene cause multiple advanced [[cancer]]s.  


The corresponding '''PTEN protein''' is found in almost all tissues in the body. The PTEN protein modifies lipids (fats) in cells by removing [[phosphate group]]s (clusters of one [[phosphor]]ous and three [[oxygen]] [[atom]]s), making the PTEN protein a type of [[enzyme]] called a [[phosphatase]]. More specifically it is a [[phosphodiesterase]] and an inhibitor of the phospho-[[AKT]] pathway by removing the 3' phosphate group of [[phosphatidylinositol (3,4,5)-trisphosphate]] (PtdIns (3,4,5)''P''<sub>3</sub>).
== Function ==


The [[Structural biology|structure]] of PTEN (solved by [[X-ray crystallography]]) reveals that it consists of a [[phosphatase]] domain, and a [[C2 domain]]: the phosphatase domain contains the [[active site]] which carries out the [[enzyme|enzymatic]] function of the protein, whilst the C2 domain allows PTEN to bind to the [[cell membrane|phospholipid membrane]] so it is able to de-phosphorylate (PtdIns (3,4,5)''P''<sub>3</sub>)
The PTEN protein is widely expressed throughout the body. PTEN protein acts as a [[phosphatase]] to dephosphorylate [[phosphatidylinositol (3,4,5)-trisphosphate]] (PtdIns (3,4,5)''P''<sub>3</sub> or PIP<sub>3</sub>). PTEN specifically catalyses the [[dephosphorylation]] of the 3` phosphate of the [[inositol]] ring in PIP<sub>3</sub>, resulting in the biphosphate product PIP<sub>2</sub> ([[PtdIns(4,5)P2]]). This dephosphorylation is important because it results in inhibition of the [[AKT]] signaling pathway, which plays an important role in regulating cellular behaviors such as cell growth, surivival, and migration.
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 is one of the most commonly lost tumour 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 also has weak protein [[phosphatase]] activity, but this activity is also crucial for its role as a  [[tumor suppressor gene|tumor suppressor]].  PTEN's protein phosphatase activity may be  involved in the regulation of the [[cell cycle]], preventing cells from growing and dividing too rapidly.<ref name="pmid15448614">{{cite journal | vauthors = Chu EC, Tarnawski AS | title = PTEN regulatory functions in tumor suppression and cell biology | journal = Medical Science Monitor | volume = 10 | issue = 10 | pages = RA235–41 | date = October 2004 | pmid = 15448614 | doi =  | url = http://www.medscimonit.com/fulltxt.php?ICID=11797 }}</ref> There have been numerous reported protein [[substrate (biochemistry)|substrates]] for PTEN, including [[IRS1]]<ref>{{cite journal | vauthors = Shi Y, Wang J, Chandarlapaty S, Cross J, Thompson C, Rosen N, Jiang X | title = PTEN is a protein tyrosine phosphatase for IRS1 | journal = Nature Structural & Molecular Biology | volume = 21 | issue = 6 | pages = 522–7 | date = June 2014 | pmid = 24814346 | pmc = 4167033 | doi = 10.1038/nsmb.2828 }}</ref> and [[Dishevelled]].<ref>{{cite journal | vauthors = Shnitsar I, Bashkurov M, Masson GR, Ogunjimi AA, Mosessian S, Cabeza EA, Hirsch CL, Trcka D, Gish G, Jiao J, Wu H, Winklbauer R, Williams RL, Pelletier L, Wrana JL, Barrios-Rodiles M | title = PTEN regulates cilia through Dishevelled | journal = Nature Communications | volume = 6 | pages = 8388 | date = September 2015 | pmid = 26399523 | pmc = 4598566 | doi = 10.1038/ncomms9388 }}</ref>


==Related conditions==
PTEN is one of the targets for drug candidates such as the [[oncomir|oncomiR]], [[MIRN21]].
PTEN mutation also causes a variety of inherited predispositions to cancer.


[[Cowden syndrome]]: Researchers have found more than 70 [[mutation]]s 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]].
== Structure ==
The [[structural biology|structure]] of the core of PTEN (solved by [[X-ray crystallography]], see figure to the upper right<ref name="pmid10555148"/>) reveals that it consists primarily of a [[phosphatase]] domain, and a [[C2 domain]]: the phosphatase domain contains the [[active site]], which carries out the [[enzyme|enzymatic]] function of the protein, while the C2 domain binds the [[cell membrane|phospholipid membrane]]. Thus PTEN binds the membrane through both its phosphatase and C2 domains, bringing the active site to the membrane-bound PIP<sub>3</sub> to dephosphorylate it.


Other disorders: Mutations in the PTEN gene cause several other disorders that, like Cowden syndrome, are characterized by the development of noncancerous tumors called [[hamartoma]]s. 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 syndrome]]s, 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.
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]].<ref>{{cite journal | vauthors = Haynie DT, Xue B | title = Superdomains in the protein structure hierarchy: The case of PTP-C2 | journal = Protein Science | volume = 24 | issue = 5 | pages = 874–82 | date = May 2015 | pmid = 25694109 | pmc = 4420535 | doi = 10.1002/pro.2664 }}</ref>


The active site of PTEN consists of three loops, the [[TI Loop]], the [[P Loop]], and the [[WPD Loop]], all named following the [[PTPB1]] nomenclature.<ref name="pmid10555148">{{cite journal | vauthors = Lee JO, Yang H, Georgescu MM, Di Cristofano A, Maehama T, Shi Y, Dixon JE, Pandolfi P, Pavletich NP | title = Crystal structure of the PTEN tumor suppressor: implications for its phosphoinositide phosphatase activity and membrane association | journal = Cell | volume = 99 | issue = 3 | pages = 323–34 | date = October 1999 | pmid = 10555148 | doi = 10.1016/S0092-8674(00)81663-3 }}</ref> Together they form an unusually deep and wide pocket which allows PTEN to accommodate the bulky [[phosphatidylinositol 3,4,5-trisphosphate]] substrate. The dephosphorylation reaction mechanism of PTEN is thought to proceed through a [[phosphoenzyme]] intermediate, with the formation of a [[phosphodiester]] bond on the active site [[cysteine]], C124.


==Further Reading==
Not present in the crystal structure of PTEN is a short 10-amino-acid unstructured region N-terminal of the phosphatase domain (from residues 6 to 15), known variously as the PIP2 Binding Domain (PBD) or PIP2 Binding Motif (PBM)<ref>{{cite journal | vauthors = Campbell RB, Liu F, Ross AH | title = Allosteric activation of PTEN phosphatase by phosphatidylinositol 4,5-bisphosphate | journal = The Journal of Biological Chemistry | volume = 278 | issue = 36 | pages = 33617–20 | date = September 2003 | pmid = 12857747 | doi = 10.1074/jbc.C300296200 }}</ref><ref>{{cite journal | vauthors = Iijima M, Huang YE, Luo HR, Vazquez F, Devreotes PN | title = Novel mechanism of PTEN regulation by its phosphatidylinositol 4,5-bisphosphate binding motif is critical for chemotaxis | journal = The Journal of Biological Chemistry | volume = 279 | issue = 16 | pages = 16606–13 | date = April 2004 | pmid = 14764604 | doi = 10.1074/jbc.M312098200 }}</ref><ref>{{cite journal | vauthors = McConnachie G, Pass I, Walker SM, Downes CP | title = Interfacial kinetic analysis of the tumour suppressor phosphatase, PTEN: evidence for activation by anionic phospholipids | journal = The Biochemical Journal | volume = 371 | issue = Pt 3 | pages = 947–55 | date = May 2003 | pmid = 12534371 | pmc = 1223325 | doi = 10.1042/BJ20021848 }}</ref> This region increases PTEN's affinity for the plasma membrane by binding to [[Phosphatidylinositol 4,5-bisphosphate]], or possibly any anionic lipid.
{{refbegin|2}}
* {{cite journal | author=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 | title=PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. | journal=Science | year=1997 | pages=1943-1947 | volume=275 | issue=5308  | id=PMID 9072974}}
* {{cite journal | author=Simpson L, Parsons R | title=PTEN: life as a tumor suppressor
| journal=Exp Cell Res | year=2001 | pages=29-41 | volume=264 | issue=1  | id=PMID 11237521}}
* {{cite journal | author=Chu EC, Tarnawski AS | title=PTEN regulatory functions in tumor suppression and cell biology | journal=Med Sci Monit | year=2004 | pages=RA235-41 | volume=10 | issue=10  | id=PMID 15448614}}
* {{cite journal | author=Eng C | title=PTEN: one gene, many syndromes | journal=Hum Mutat | year=2003 | pages=183-98 | volume=22 | issue=3  | id=PMID 12938083}}
* {{cite journal | author=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 | title=The PTEN/PI3K pathway governs normal vascular development and tumor angiogenesis | journal=Genes Dev | year=2005 | pages=2054–65 | volume=19 | issue=17  | id=PMID 16107612}}
* {{cite journal | author=Leslie NR, Downes CP | title=PTEN function: how normal cells control it and tumour cells lose it | journal=Biochem J | year=2004 | pages=1–11 | volume=382 | issue=Pt 1  | id=PMID 15193142}}
* {{cite journal | author=Pilarski R, Eng C | title=Will the real Cowden syndrome please stand up (again)? Expanding mutational and clinical spectra of the PTEN hamartoma tumour syndrome | journal=J Med Genet | year=2004 | pages=323-6 | volume=41 | issue=5  | id=PMID 15121767}}
* {{cite journal | author=Sansal I, Sellers WR | title=The biology and clinical relevance of the PTEN tumor suppressor pathway | journal=J Clin Oncol | year=2004 | pages=2954–63 | volume=22 | issue=14  | id=PMID 15254063}}
* {{cite journal | author=Waite KA, Eng C | title=Protean PTEN: form and function | journal=Am J Hum Genet | year=2002 | pages=829-44 | volume=70 | issue=4  | id=PMID 11875759}}
* {{cite journal | author=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 | title=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 | journal=Am J Hum Genet | year=2003 | pages=404-11 | volume=73 | issue=2  | id=PMID 12844284}}
{{refend}}


==External links==
Also not present in the crystal structure is the [[Intrinsically disordered proteins|intrinsically disordered]] C-terminal region (CTR) (spanning residues 353-403). The CTR is constitutively [[Phosphorylation|phosphorylated]] at various positions that effect various aspects of PTEN, including its ability to bind to lipid membranes, and also act as either a protein or lipid phosphatase.<ref>{{cite journal | vauthors = Rahdar M, Inoue T, Meyer T, Zhang J, Vazquez F, Devreotes PN | title = A phosphorylation-dependent intramolecular interaction regulates the membrane association and activity of the tumor suppressor PTEN | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 2 | pages = 480–5 | date = January 2009 | pmid = 19114656 | pmc = 2626728 | doi = 10.1073/pnas.0811212106 }}</ref><ref name=":0">{{cite journal | vauthors = Masson GR, Perisic O, Burke JE, Williams RL | title = The intrinsically disordered tails of PTEN and PTEN-L have distinct roles in regulating substrate specificity and membrane activity | journal = The Biochemical Journal | volume = 473 | issue = 2 | pages = 135–44 | date = January 2016 | pmid = 26527737 | pmc = 4700475 | doi = 10.1042/BJ20150931 }}</ref>
* [http://macromoleculeinsights.com/pten.php The PTEN Protein]
 
* [http://www.genecards.org/cgi-bin/carddisp?PTEN GeneCard]
Additionally, PTEN can also be expressed as PTEN-L<ref>{{cite journal | vauthors = Hopkins BD, Fine B, Steinbach N, Dendy M, Rapp Z, Shaw J, Pappas K, Yu JS, Hodakoski C, Mense S, Klein J, Pegno S, Sulis ML, Goldstein H, Amendolara B, Lei L, Maurer M, Bruce J, Canoll P, Hibshoosh H, Parsons R | title = A secreted PTEN phosphatase that enters cells to alter signaling and survival | journal = Science | volume = 341 | issue = 6144 | pages = 399–402 | date = July 2013 | pmid = 23744781 | pmc = 3935617 | doi = 10.1126/science.1234907 }}</ref> (known as PTEN-Long, or PTEN-α<ref>{{cite journal | vauthors = Liang H, He S, Yang J, Jia X, Wang P, Chen X, Zhang Z, Zou X, McNutt MA, Shen WH, Yin Y | title = PTENα, a PTEN isoform translated through alternative initiation, regulates mitochondrial function and energy metabolism | journal = Cell Metabolism | volume = 19 | issue = 5 | pages = 836–48 | date = May 2014 | pmid = 24768297 | pmc = 4097321 | doi = 10.1016/j.cmet.2014.03.023 }}</ref>), a [[leucine]] initiator alternative start site variant, which adds an additional 173 amino acids to the N-terminus of PTEN. The exact role of this 173-amino acid extension is not yet known, either causing PTEN to be secreted from the cell, or to interact with the mitochondria. The N-terminal extension has been predicted to be largely disordered,<ref>{{cite journal | vauthors = Malaney P, Uversky VN, Davé V | title = The PTEN Long N-tail is intrinsically disordered: increased viability for PTEN therapy | journal = Molecular bioSystems | volume = 9 | issue = 11 | pages = 2877–88 | date = November 2013 | pmid = 24056727 | doi = 10.1039/c3mb70267g }}</ref> although there is evidence that there is some structure in the last twenty amino acids of the extension (most proximal to the start [[methionine]] of PTEN).<ref name=":0" />
* {{UMichOPM|protein|pdbid|1d5r}}  
 
== Clinical significance ==
 
=== Cancer ===
 
PTEN is one of the most commonly lost [[Tumor suppressor gene|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.<ref name="pmid16079851">{{cite journal | vauthors = Chen Z, Trotman LC, Shaffer D, Lin HK, Dotan ZA, Niki M, Koutcher JA, Scher HI, Ludwig T, Gerald W, Cordon-Cardo C, Pandolfi PP | title = Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis | journal = Nature | volume = 436 | issue = 7051 | pages = 725–30 | date = August 2005 | pmid = 16079851 | pmc = 1939938 | doi = 10.1038/nature03918 }}</ref>
 
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 [[mutation]]s in the ''PTEN'' gene in people with [[Cowden syndrome]].{{Citation needed|date=September 2013}} These mutations can be changes in a small number of [[base pairs]] or, in some cases, deletions of a large number of base pairs.{{Citation needed|date=September 2013}} 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]].<ref name="JMG1">{{cite journal | vauthors = Pilarski R, Eng C | title = Will the real Cowden syndrome please stand up (again)? Expanding mutational and clinical spectra of the PTEN hamartoma tumour syndrome | journal = Journal of Medical Genetics | volume = 41 | issue = 5 | pages = 323–6 | date = May 2004 | pmid = 15121767 | pmc = 1735782 | doi = 10.1136/jmg.2004.018036 }}</ref>
 
Mutations in the ''PTEN'' gene cause several other disorders that, like Cowden syndrome, are characterized by the development of non-cancerous tumors called [[hamartoma]]s. These disorders include [[Bannayan-Riley-Ruvalcaba syndrome]] and [[Proteus-like syndrome]]. Together, the disorders caused by ''PTEN'' mutations are called [[PTEN hamartoma tumor syndrome]]s, 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.<ref name="JMG1"/>
 
=== Brain function and autism ===
 
Defects of the ''PTEN'' gene have been cited to be a potential cause of [[autism]] spectrum disorders.<ref name="pmid22900024">{{cite journal | vauthors = Napoli E, Ross-Inta C, Wong S, Hung C, Fujisawa Y, Sakaguchi D, Angelastro J, Omanska-Klusek A, Schoenfeld R, Giulivi C | title = Mitochondrial dysfunction in Pten haplo-insufficient mice with social deficits and repetitive behavior: interplay between Pten and p53 | journal = PLoS One | volume = 7 | issue = 8 | pages = e42504 | year = 2012 | pmid = 22900024 | pmc = 3416855 | doi = 10.1371/journal.pone.0042504 }}</ref> 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]].<ref name="pmid22900024"/>
 
Patients with defective ''PTEN'' can develop cerebellar mass lesions called dysplastic gangliocytomas or [[Lhermitte–Duclos disease]].<ref name="JMG1"/>
 
=== Cell regeneration ===
 
PTEN's strong link to cell growth inhibition is being studied as a possible [[Biological target|therapeutic target]] in tissues that do not traditionally regenerate in mature animals, such as central neurons. PTEN [[deletion (genetics)|deletion mutants]] have recently<ref>{{cite news|url=http://www.latimes.com/health/boostershots/la-heb-rodent-20100813,0,5830521.story |title=Rodent of the Week: Nerves regenerated after spinal cord injury|date=August 13, 2010 | work=The Los Angeles Times}}</ref> been shown to allow nerve regeneration in mice.<ref name="pmid20694004">{{cite journal | vauthors = Liu K, Lu Y, Lee JK, Samara R, Willenberg R, Sears-Kraxberger I, Tedeschi A, Park KK, Jin D, Cai B, Xu B, Connolly L, Steward O, Zheng B, He Z | title = PTEN deletion enhances the regenerative ability of adult corticospinal neurons | journal = Nature Neuroscience | volume = 13 | issue = 9 | pages = 1075–81 | date = September 2010 | pmid = 20694004 | pmc = 2928871 | doi = 10.1038/nn.2603 }}</ref>
 
==As a drug target==
 
===PTEN inhibitors===
[[Bisperoxovanadium]] compounds, have a neuroprotective effect after CNS injury.<ref name=Walker2012>{{cite journal | vauthors = Walker CL, Walker MJ, Liu NK, Risberg EC, Gao X, Chen J, Xu XM | title = Systemic bisperoxovanadium activates Akt/mTOR, reduces autophagy, and enhances recovery following cervical spinal cord injury | journal = PLoS One | volume = 7 | issue = 1 | pages = e30012 | year = 2012 | pmid = 22253859 | pmc = 3254642 | doi = 10.1371/journal.pone.0030012 }}</ref>  PTEN inhibited by [[Sarcopoterium]].<ref name="pmid24882728">{{cite journal | vauthors = Rozenberg K, Smirin P, Sampson SR, Rosenzweig T | title = Insulin-sensitizing and insulin-mimetic activities of Sarcopoterium spinosum extract | journal = Journal of Ethnopharmacology | volume = 155 | issue = 1 | pages = 362–72 | date = August 2014 | pmid = 24882728 | doi = 10.1016/j.jep.2014.05.030 }}</ref>
 
===PTEN agonists===
e.g. [[rapamycin]], [[sirolimus]] and [[temsirolimus]].<ref>[http://www.google.com/patents/US20110189169 Combination of hgf inhibitor and pten agonist to treat cancer US 20110189169 A1]</ref>
 
== Cell lines ==
 
Cell lines with known PTEN mutations include:
* prostate: [[LNCaP]], [[PC-3]]
* kidney: [[786-O]]
* glioblastoma: [[U87|U87MG]]<ref name="pmid9072974">{{cite journal | vauthors = 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 | title = PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer | journal = Science | volume = 275 | issue = 5308 | pages = 1943–7 | date = March 1997 | pmid = 9072974 | doi = 10.1126/science.275.5308.1943 }}</ref>
* breast : [[MB-MDA-468]], [[BT549]]<ref name="pmid9072974"/>
* bladder: [[J82]], [[UMUC-3]]
 
== Interactions ==
 
PTEN (gene) has been shown to [[Protein-protein interaction|interact]] with:
{{div col|colwidth=18em}}
* [[CSNK2A2]],<ref name=pmid12297295>{{cite journal | vauthors = Miller SJ, Lou DY, Seldin DC, Lane WS, Neel BG | title = Direct identification of PTEN phosphorylation sites | journal = FEBS Letters | volume = 528 | issue = 1–3 | pages = 145–53 | date = September 2002 | pmid = 12297295 | doi = 10.1016/S0014-5793(02)03274-X }}</ref>
* [[Casein kinase 2, alpha 1|CSNK2A1]],<ref name=pmid12297295/>
* [[MAGI3]]<ref name=pmid10748157>{{cite journal | vauthors = Wu Y, Dowbenko D, Spencer S, Laura R, Lee J, Gu Q, Lasky LA | title = Interaction of the tumor suppressor PTEN/MMAC with a PDZ domain of MAGI3, a novel membrane-associated guanylate kinase | journal = The Journal of Biological Chemistry | volume = 275 | issue = 28 | pages = 21477–85 | date = July 2000 | pmid = 10748157 | doi = 10.1074/jbc.M909741199 }}</ref>
* [[Major vault protein|MVP]],<ref name=pmid12177006>{{cite journal | vauthors = Yu Z, Fotouhi-Ardakani N, Wu L, Maoui M, Wang S, Banville D, Shen SH | title = PTEN associates with the vault particles in HeLa cells | journal = The Journal of Biological Chemistry | volume = 277 | issue = 43 | pages = 40247–52 | date = October 2002 | pmid = 12177006 | doi = 10.1074/jbc.M207608200 }}</ref>
* [[NEDD4]],<ref name=pmid18498243>{{cite journal | vauthors = Wang X, Shi Y, Wang J, Huang G, Jiang X | title = Crucial role of the C-terminus of PTEN in antagonizing NEDD4-1-mediated PTEN ubiquitination and degradation | journal = The Biochemical Journal | volume = 414 | issue = 2 | pages = 221–9 | date = September 2008 | pmid = 18498243 | doi = 10.1042/BJ20080674 }}</ref>
* [[Androgen receptor|NR3C4]],<ref name=pmid15205473>{{cite journal | vauthors = Lin HK, Hu YC, Lee DK, Chang C | title = Regulation of androgen receptor signaling by PTEN (phosphatase and tensin homolog deleted on chromosome 10) tumor suppressor through distinct mechanisms in prostate cancer cells | journal = Molecular Endocrinology | volume = 18 | issue = 10 | pages = 2409–23 | date = October 2004 | pmid = 15205473 | doi = 10.1210/me.2004-0117 }}</ref>
* [[P53]],<ref name=pmid12620407>{{cite journal | vauthors = Freeman DJ, Li AG, Wei G, Li HH, Kertesz N, Lesche R, Whale AD, Martinez-Diaz H, Rozengurt N, Cardiff RD, Liu X, Wu H | title = PTEN tumor suppressor regulates p53 protein levels and activity through phosphatase-dependent and -independent mechanisms | journal = Cancer Cell | volume = 3 | issue = 2 | pages = 117–30 | date = February 2003 | pmid = 12620407 | doi = 10.1016/S1535-6108(03)00021-7 }}</ref> and
* [[PTK2]].<ref name=pmid10400703>{{cite journal | vauthors = Tamura M, Gu J, Danen EH, Takino T, Miyamoto S, Yamada KM | title = PTEN interactions with focal adhesion kinase and suppression of the extracellular matrix-dependent phosphatidylinositol 3-kinase/Akt cell survival pathway | journal = The Journal of Biological Chemistry | volume = 274 | issue = 29 | pages = 20693–703 | date = July 1999 | pmid = 10400703 | doi = 10.1074/jbc.274.29.20693 }}</ref><ref name=pmid11857088>{{cite journal | vauthors = Haier J, Nicolson GL | title = PTEN regulates tumor cell adhesion of colon carcinoma cells under dynamic conditions of fluid flow | journal = Oncogene | volume = 21 | issue = 9 | pages = 1450–60 | date = February 2002 | pmid = 11857088 | doi = 10.1038/sj.onc.1205213 }}</ref>
{{div col end}}
 
== See also ==
* [[Multiple hamartoma syndrome]]
 
== References ==
{{Reflist|35em}}
 
== Further reading ==
{{Refbegin|35em}}
* {{cite journal | vauthors = 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 | title = PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer | journal = Science | volume = 275 | issue = 5308 | pages = 1943–7 | date = March 1997 | pmid = 9072974 | doi = 10.1126/science.275.5308.1943 }}
* {{cite journal | vauthors = Simpson L, Parsons R | title = PTEN: life as a tumor suppressor | journal = Experimental Cell Research | volume = 264 | issue = 1 | pages = 29–41 | date = March 2001 | pmid = 11237521 | doi = 10.1006/excr.2000.5130 }}
* {{cite journal | vauthors = Eng C | title = PTEN: one gene, many syndromes | journal = Human Mutation | volume = 22 | issue = 3 | pages = 183–98 | date = September 2003 | pmid = 12938083 | doi = 10.1002/humu.10257 }}
* {{cite journal | vauthors = 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 | title = The PTEN/PI3K pathway governs normal vascular development and tumor angiogenesis | journal = Genes & Development | volume = 19 | issue = 17 | pages = 2054–65 | date = September 2005 | pmid = 16107612 | pmc = 1199575 | doi = 10.1101/gad.1308805 }}
* {{cite journal | vauthors = Leslie NR, Downes CP | title = PTEN function: how normal cells control it and tumour cells lose it | journal = The Biochemical Journal | volume = 382 | issue = Pt 1 | pages = 1–11 | date = August 2004 | pmid = 15193142 | pmc = 1133909 | doi = 10.1042/BJ20040825 }}
* {{cite journal | vauthors = Sansal I, Sellers WR | title = The biology and clinical relevance of the PTEN tumor suppressor pathway | journal = Journal of Clinical Oncology | volume = 22 | issue = 14 | pages = 2954–63 | date = July 2004 | pmid = 15254063 | doi = 10.1200/JCO.2004.02.141 }}
* {{cite journal | vauthors = Waite KA, Eng C | title = Protean PTEN: form and function | journal = American Journal of Human Genetics | volume = 70 | issue = 4 | pages = 829–44 | date = April 2002 | pmid = 11875759 | pmc = 379112 | doi = 10.1086/340026 }}
* {{cite journal | vauthors = 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 | title = 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 | journal = American Journal of Human Genetics | volume = 73 | issue = 2 | pages = 404–11 | date = August 2003 | pmid = 12844284 | pmc = 1180378 | doi = 10.1086/377109 }}
* {{cite journal | vauthors = Ji SP, Zhang Y, Van Cleemput J, Jiang W, Liao M, Li L, Wan Q, Backstrom JR, Zhang X | title = Disruption of PTEN coupling with 5-HT2C receptors suppresses behavioral responses induced by drugs of abuse | journal = Nature Medicine | volume = 12 | issue = 3 | pages = 324–9 | date = March 2006 | pmid = 16474401 | doi = 10.1038/nm1349 }}
{{Refend}}
 
== External links ==
* [https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=phts  GeneReviews/NCBI/NIH/UW entry on PTEN Hamartoma Tumor Syndrome (PHTS)]
* {{MeshName|PTEN+Protein}}
* {{MeshName|PTEN+Protein}}
* {{Cite web| url = https://www.genecards.org/cgi-bin/carddisp.pl?gene=PTEN | title = PTEN Gene - phosphatase and tensin homolog | author = | authorlink = | vauthors = | date = | format = | work = GeneCards | publisher = The Weizmann Institute of Science | pages = | archiveurl =https://web.archive.org/web/20071008150651/http://www.genecards.org/cgi-bin/carddisp.pl?gene=PTEN| archivedate =2007-10-08| quote = | dead-url = yes | accessdate = 2009-03-12}}
* {{Cite web| url =http://www.alzforum.org/res/com/gen/alzgene/geneoverview.asp?geneid=351| title =Gene overview of all published AD-association studies for PTEN| author =| authorlink =| vauthors =| date =| format =| work =Alzforum: AlzGene| publisher =Alzheimer Research Forum| pages =| archiveurl =https://web.archive.org/web/20090210213449/http://www.alzforum.org/res/com/gen/alzgene/geneoverview.asp?geneid=351| archivedate =2009-02-10| quote =| accessdate =2009-03-12| deadurl =yes| df =}}
*[http://www.ucdmc.ucdavis.edu/publish/news/mindinstitute/6866 Research shows gene defect's role in autism-like behavior]
*[https://www.youtube.com/watch?v=11uWdukMhTc Dance Your PhD 2017 : A Story of Tumor Suppression] Deepti Mathur. PTEN and cancer explained in dance. A metabolic pathway uses glutamine to create a component of DNA. This pathway is regulated in part by PTEN. Loss of PTEN allows the pathway to go into overdrive, leading to cancer. A drug that interrupts the PTEN pathway preferentially destroys cancer cells.


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{{DEFAULTSORT:Pten (Gene)}}
[[Category:Tumor suppressor genes]]
[[Category:Tumor suppressor genes]]
[[Category:Peripheral membrane proteins]]
[[Category:Peripheral membrane proteins]]
[[Category:EC 3.1.3]]
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Latest revision as of 23:47, 18 November 2018

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Identifiers
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External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
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File:PTEN.png
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. Genes corresponding to PTEN (orthologs)[3] have been identified in most mammals for which complete genome data are available.

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.[4] It is a target of many cancer drugs.

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.[5]

Function

The PTEN protein is widely expressed throughout 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 dephosphorylation 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, which plays an important role in regulating cellular behaviors such as cell growth, surivival, and migration.

PTEN also has weak protein phosphatase activity, but this activity is also crucial for its role as a tumor suppressor. PTEN's protein phosphatase activity may be involved in the regulation of the cell cycle, preventing cells from growing and dividing too rapidly.[4] There have been numerous reported protein substrates for PTEN, including IRS1[6] and Dishevelled.[7]

PTEN is one of the targets for drug candidates such as the oncomiR, MIRN21.

Structure

The structure of the core of PTEN (solved by X-ray crystallography, see figure to the upper right[1]) reveals that it consists primarily 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 both its phosphatase and C2 domains, bringing the active site to the membrane-bound PIP3 to dephosphorylate 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.[8]

The active site of PTEN consists of three loops, the TI Loop, the P Loop, and the WPD Loop, all named following the PTPB1 nomenclature.[1] Together they form an unusually deep and wide pocket which allows PTEN to accommodate the bulky phosphatidylinositol 3,4,5-trisphosphate substrate. The dephosphorylation reaction mechanism of PTEN is thought to proceed through a phosphoenzyme intermediate, with the formation of a phosphodiester bond on the active site cysteine, C124.

Not present in the crystal structure of PTEN is a short 10-amino-acid unstructured region N-terminal of the phosphatase domain (from residues 6 to 15), known variously as the PIP2 Binding Domain (PBD) or PIP2 Binding Motif (PBM)[9][10][11] This region increases PTEN's affinity for the plasma membrane by binding to Phosphatidylinositol 4,5-bisphosphate, or possibly any anionic lipid.

Also not present in the crystal structure is the intrinsically disordered C-terminal region (CTR) (spanning residues 353-403). The CTR is constitutively phosphorylated at various positions that effect various aspects of PTEN, including its ability to bind to lipid membranes, and also act as either a protein or lipid phosphatase.[12][13]

Additionally, PTEN can also be expressed as PTEN-L[14] (known as PTEN-Long, or PTEN-α[15]), a leucine initiator alternative start site variant, which adds an additional 173 amino acids to the N-terminus of PTEN. The exact role of this 173-amino acid extension is not yet known, either causing PTEN to be secreted from the cell, or to interact with the mitochondria. The N-terminal extension has been predicted to be largely disordered,[16] although there is evidence that there is some structure in the last twenty amino acids of the extension (most proximal to the start methionine of PTEN).[13]

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.[17]

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.[citation needed] These mutations can be changes in a small number of base pairs or, in some cases, deletions of a large number of base pairs.[citation needed] 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.[18]

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.[18]

Brain function and autism

Defects of the PTEN gene have been cited to be a potential cause of autism spectrum disorders.[19] 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.[19]

Patients with defective PTEN can develop cerebellar mass lesions called dysplastic gangliocytomas or Lhermitte–Duclos disease.[18]

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[20] been shown to allow nerve regeneration in mice.[21]

As a drug target

PTEN inhibitors

Bisperoxovanadium compounds, have a neuroprotective effect after CNS injury.[22] PTEN inhibited by Sarcopoterium.[23]

PTEN agonists

e.g. rapamycin, sirolimus and temsirolimus.[24]

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 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". Nature Genetics. 15 (4): 356–62. doi:10.1038/ng0497-356. PMID 9090379.
  3. ↑ "OrthoMaM phylogenetic marker: PTEN coding sequence".
  4. ↑ 4.0 4.1 Chu EC, Tarnawski AS (October 2004). "PTEN regulatory functions in tumor suppression and cell biology". Medical Science Monitor. 10 (10): RA235–41. PMID 15448614.
  5. ↑ "Entrez Gene: PTEN phosphatase and tensin homolog (mutated in multiple advanced cancers 1)".
  6. ↑ Shi Y, Wang J, Chandarlapaty S, Cross J, Thompson C, Rosen N, Jiang X (June 2014). "PTEN is a protein tyrosine phosphatase for IRS1". Nature Structural & Molecular Biology. 21 (6): 522–7. doi:10.1038/nsmb.2828. PMC 4167033. PMID 24814346.
  7. ↑ Shnitsar I, Bashkurov M, Masson GR, Ogunjimi AA, Mosessian S, Cabeza EA, Hirsch CL, Trcka D, Gish G, Jiao J, Wu H, Winklbauer R, Williams RL, Pelletier L, Wrana JL, Barrios-Rodiles M (September 2015). "PTEN regulates cilia through Dishevelled". Nature Communications. 6: 8388. doi:10.1038/ncomms9388. PMC 4598566. PMID 26399523.
  8. ↑ Haynie DT, Xue B (May 2015). "Superdomains in the protein structure hierarchy: The case of PTP-C2". Protein Science. 24 (5): 874–82. doi:10.1002/pro.2664. PMC 4420535. PMID 25694109.
  9. ↑ Campbell RB, Liu F, Ross AH (September 2003). "Allosteric activation of PTEN phosphatase by phosphatidylinositol 4,5-bisphosphate". The Journal of Biological Chemistry. 278 (36): 33617–20. doi:10.1074/jbc.C300296200. PMID 12857747.
  10. ↑ Iijima M, Huang YE, Luo HR, Vazquez F, Devreotes PN (April 2004). "Novel mechanism of PTEN regulation by its phosphatidylinositol 4,5-bisphosphate binding motif is critical for chemotaxis". The Journal of Biological Chemistry. 279 (16): 16606–13. doi:10.1074/jbc.M312098200. PMID 14764604.
  11. ↑ McConnachie G, Pass I, Walker SM, Downes CP (May 2003). "Interfacial kinetic analysis of the tumour suppressor phosphatase, PTEN: evidence for activation by anionic phospholipids". The Biochemical Journal. 371 (Pt 3): 947–55. doi:10.1042/BJ20021848. PMC 1223325. PMID 12534371.
  12. ↑ Rahdar M, Inoue T, Meyer T, Zhang J, Vazquez F, Devreotes PN (January 2009). "A phosphorylation-dependent intramolecular interaction regulates the membrane association and activity of the tumor suppressor PTEN". Proceedings of the National Academy of Sciences of the United States of America. 106 (2): 480–5. doi:10.1073/pnas.0811212106. PMC 2626728. PMID 19114656.
  13. ↑ 13.0 13.1 Masson GR, Perisic O, Burke JE, Williams RL (January 2016). "The intrinsically disordered tails of PTEN and PTEN-L have distinct roles in regulating substrate specificity and membrane activity". The Biochemical Journal. 473 (2): 135–44. doi:10.1042/BJ20150931. PMC 4700475. PMID 26527737.
  14. ↑ Hopkins BD, Fine B, Steinbach N, Dendy M, Rapp Z, Shaw J, Pappas K, Yu JS, Hodakoski C, Mense S, Klein J, Pegno S, Sulis ML, Goldstein H, Amendolara B, Lei L, Maurer M, Bruce J, Canoll P, Hibshoosh H, Parsons R (July 2013). "A secreted PTEN phosphatase that enters cells to alter signaling and survival". Science. 341 (6144): 399–402. doi:10.1126/science.1234907. PMC 3935617. PMID 23744781.
  15. ↑ Liang H, He S, Yang J, Jia X, Wang P, Chen X, Zhang Z, Zou X, McNutt MA, Shen WH, Yin Y (May 2014). "PTENα, a PTEN isoform translated through alternative initiation, regulates mitochondrial function and energy metabolism". Cell Metabolism. 19 (5): 836–48. doi:10.1016/j.cmet.2014.03.023. PMC 4097321. PMID 24768297.
  16. ↑ Malaney P, Uversky VN, Davé V (November 2013). "The PTEN Long N-tail is intrinsically disordered: increased viability for PTEN therapy". Molecular bioSystems. 9 (11): 2877–88. doi:10.1039/c3mb70267g. PMID 24056727.
  17. ↑ Chen Z, Trotman LC, Shaffer D, Lin HK, Dotan ZA, Niki M, Koutcher JA, Scher HI, Ludwig T, Gerald W, Cordon-Cardo C, Pandolfi PP (August 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.
  18. ↑ 18.0 18.1 18.2 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.
  19. ↑ 19.0 19.1 Napoli E, Ross-Inta C, Wong S, Hung C, Fujisawa Y, Sakaguchi D, Angelastro J, Omanska-Klusek A, Schoenfeld R, Giulivi C (2012). "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.
  20. ↑ "Rodent of the Week: Nerves regenerated after spinal cord injury". The Los Angeles Times. August 13, 2010.
  21. ↑ Liu K, Lu Y, Lee JK, Samara R, Willenberg R, Sears-Kraxberger I, Tedeschi A, Park KK, Jin D, Cai B, Xu B, Connolly L, Steward O, Zheng B, He Z (September 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.
  22. ↑ Walker CL, Walker MJ, Liu NK, Risberg EC, Gao X, Chen J, Xu XM (2012). "Systemic bisperoxovanadium activates Akt/mTOR, reduces autophagy, and enhances recovery following cervical spinal cord injury". PLoS One. 7 (1): e30012. doi:10.1371/journal.pone.0030012. PMC 3254642. PMID 22253859.
  23. ↑ Rozenberg K, Smirin P, Sampson SR, Rosenzweig T (August 2014). "Insulin-sensitizing and insulin-mimetic activities of Sarcopoterium spinosum extract". Journal of Ethnopharmacology. 155 (1): 362–72. doi:10.1016/j.jep.2014.05.030. PMID 24882728.
  24. ↑ Combination of hgf inhibitor and pten agonist to treat cancer US 20110189169 A1
  25. ↑ 25.0 25.1 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 (March 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.
  26. ↑ 26.0 26.1 Miller SJ, Lou DY, Seldin DC, Lane WS, Neel BG (September 2002). "Direct identification of PTEN phosphorylation sites". FEBS Letters. 528 (1–3): 145–53. doi:10.1016/S0014-5793(02)03274-X. PMID 12297295.
  27. ↑ Wu Y, Dowbenko D, Spencer S, Laura R, Lee J, Gu Q, Lasky LA (July 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.
  28. ↑ Yu Z, Fotouhi-Ardakani N, Wu L, Maoui M, Wang S, Banville D, Shen SH (October 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.
  29. ↑ Wang X, Shi Y, Wang J, Huang G, Jiang X (September 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.
  30. ↑ Lin HK, Hu YC, Lee DK, Chang C (October 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.
  31. ↑ Freeman DJ, Li AG, Wei G, Li HH, Kertesz N, Lesche R, Whale AD, Martinez-Diaz H, Rozengurt N, Cardiff RD, Liu X, Wu H (February 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.
  32. ↑ Tamura M, Gu J, Danen EH, Takino T, Miyamoto S, Yamada KM (July 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.
  33. ↑ Haier J, Nicolson GL (February 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.

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