PTEN Regulation

Li Y, Tsang CK, Wang S, Li XX, Yang Y, Fu L, Huang W, Li M, Wang HY, Zheng XF. MAF1 suppresses AKT-mTOR signaling and liver cancer through activation of PTEN transcription. Hepatology. 2016 Jun;63(6):1928–42. PMID: 26910647; PMCID: PMC5021206.; Leslie NR, Kriplani N, Hermida MA, Alvarez-Garcia V, Wise HM. The PTEN protein: cellular localization and post-translational regulation. Biochem Soc Trans. 2016 Feb;44(1):273–8. doi: 10.1042/bst20150224. PMID: 26862215.; Verrastro I, Tveen-Jensen K, Woscholski R, Spickett CM, Pitt AR. Reversible oxidation of phosphatase and tensin homolog (PTEN) alters its interactions with signaling and regulatory proteins. Free Radic Biol Med. 2016 Jan;90():24–34. doi: 10.1016/j.freeradbiomed.2015.11.004. PMID: 26561776.; Shen S, Guo M, Xiong Z, Yu Y, Zhao X, Zhang F, Chen G. AIF inhibits tumor metastasis by protecting PTEN from oxidation. EMBO Reports. 2015 Sep 28;16(11):1563–80. doi: 10.15252/embr.201540536.; Meng Z, Jia LF, Gan YH. PTEN activation through K163 acetylation by inhibiting HDAC6 contributes to tumour inhibition. Oncogene. 2016 May 05;35(18):2333–44. doi: 10.1038/onc.2015.293. PMID: 26279303.; Yuan L, Lv Y, Li H, Gao H, Song S, Zhang Y, Xing G, Kong X, Wang L, Li Y, Zhou T, Gao D, Xiao ZX, Yin Y, Wei W, He F, Zhang L. Deubiquitylase OTUD3 regulates PTEN stability and suppresses tumorigenesis. Nat Cell Biol. 2015 Sep;17(9):1169–81. doi: 10.1038/ncb3218. PMID: 26280536.; Lee MS, Jeong MH, Lee HW, Han HJ, Ko A, Hewitt SM, Kim JH, Chun KH, Chung JY, Lee C, Cho H, Song J. PI3K/AKT activation induces PTEN ubiquitination and destabilization accelerating tumourigenesis. Nat Commun. 2015 Jul 17;6():7769. PMID: 26183061; PMCID: PMC4518267.; Lang V, Aillet F, Da Silva-Ferrada E, Xolalpa W, Zabaleta L, Rivas C, Rodriguez MS. Analysis of PTEN ubiquitylation and SUMOylation using molecular traps. Methods. 2015 May;77-78():112–8. doi: 10.1016/j.ymeth.2014.09.001. PMID: 25224693.; Tan PL, Shavlakadze T, Grounds MD, Arthur PG. Differential thiol oxidation of the signaling proteins Akt, PTEN or PP2A determines whether Akt phosphorylation is enhanced or inhibited by oxidative stress in C2C12 myotubes derived from skeletal muscle. The International Journal of Biochemistry & Cell Biology. 2015 May;62():72–9. doi: 10.1016/j.biocel.2015.02.015.; Lin CH, Liu SY, Lee EH. SUMO modification of Akt regulates global SUMOylation and substrate SUMOylation specificity through Akt phosphorylation of Ubc9 and SUMO1. Oncogene. 2016 Feb 04;35(5):595–607. doi: 10.1038/onc.2015.115. PMID: 25867063.; Uygur B, Abramo K, Leikina E, Vary C, Liaw L, Wu WS. SLUG is a direct transcriptional repressor of PTEN tumor suppressor. Prostate. 2015 Jun 15;75(9):907–16. PMID: 25728608; PMCID: PMC4654464.; Collaud S, Tischler V, Atanassoff A, Wiedl T, Komminoth P, Oehlschlegel C, Weder W, Soltermann A. Lung neuroendocrine tumors: correlation of ubiquitinylation and sumoylation with nucleo-cytosolic partitioning of PTEN. BMC Cancer. 2015 Feb 20;15():74. PMID: 25884169; PMCID: PMC4350902.; Li N, Zhang Y, Han X, Liang K, Wang J, Feng L, Wang W, Songyang Z, Lin C, Yang L, Yu Y, Chen J. Poly-ADP ribosylation of PTEN by tankyrases promotes PTEN degradation and tumor growth. Genes Dev. 2015 Jan 15;29(2):157–70. PMID: 25547115; PMCID: PMC4298135.; Wang W, Chen Y, Wang S, Hu N, Cao Z, Wang W, Tong T, Zhang X. PIASxa Ligase Enhances SUMO1 Modification of PTEN Protein as a SUMO E3 Ligase. Journal of Biological Chemistry. 2014 Feb;289(6):3217–30. doi: 10.1074/jbc.m113.508515.; Tay Y, Rinn J, Pandolfi PP. The multilayered complexity of ceRNA crosstalk and competition. Nature. 2014 Jan 16;505(7483):344–52. PMID: 24429633; PMCID: PMC4113481.; Hodakoski C, Hopkins BD, Barrows D, Mense SM, Keniry M, Anderson KE, Kern PA, Hawkins PT, Stephens LR, Parsons R. Regulation of PTEN inhibition by the pleckstrin homology domain of P-REX2 during insulin signaling and glucose homeostasis. Proc Natl Acad Sci U S A. 2014 Jan 07;111(1):155–60. PMID: 24367090; PMCID: PMC3890808.; Zhang J, Zhang P, Wei Y, Piao HL, Wang W, Maddika S, Wang M, Chen D, Sun Y, Hung MC, Chen J, Ma L. Deubiquitylation and stabilization of PTEN by USP13. Nat Cell Biol. 2013 Dec;15(12):1486–94. PMID: 24270891; PMCID: PMC3951854.; Cai J, Fang L, Huang Y, Li R, Yuan J, Yang Y, Zhu X, Chen B, Wu J, Li M. miR-205 targets PTEN and PHLPP2 to augment AKT signaling and drive malignant phenotypes in non-small cell lung cancer. Cancer Res. 2013 Sep 01;73(17):5402–15. doi: 10.1158/0008-5472.can-13-0297. PMID: 23856247.; Bassi C, Ho J, Srikumar T, Dowling RJ, Gorrini C, Miller SJ, Mak TW, Neel BG, Raught B, Stambolic V. Nuclear PTEN controls DNA repair and sensitivity to genotoxic stress. Science. 2013 Jul 26;341(6144):395–9. PMID: 23888040; PMCID: PMC5087104.; Da Silva-Ferrada E, Xolalpa W, Lang V, Aillet F, Martin-Ruiz I, de la Cruz-Herrera CF, Lopitz-Otsoa F, Carracedo A, Goldenberg SJ, Rivas C, England P, Rodríguez MS. Analysis of SUMOylated proteins using SUMO-traps. Scientific Reports. 2013 Apr 22;3(1):1690. doi: 10.1038/srep01690.; Lee JT, Shan J, Zhong J, Li M, Zhou B, Zhou A, Parsons R, Gu W. RFP-mediated ubiquitination of PTEN modulates its effect on AKT activation. Cell Res. 2013 Apr;23(4):552–64. PMID: 23419514; PMCID: PMC3616435.; Shenoy SS, Nanda H, Lösche M. Membrane association of the PTEN tumor suppressor: Electrostatic interaction with phosphatidylserine-containing bilayers and regulatory role of the C-terminal tail. Journal of Structural Biology. 2012 Dec;180(3):394–408. doi: 10.1016/j.jsb.2012.10.003.; González-Santamaría J, Campagna M, Ortega-Molina A, Marcos-Villar L, de la Cruz-Herrera CF, González D, Gallego P, Lopitz-Otsoa F, Esteban M, Rodríguez MS, Serrano M, Rivas C. Regulation of the tumor suppressor PTEN by SUMO. Cell Death & Disease. 2012 Sep 27;3(9):e393. doi: 10.1038/cddis.2012.135.; Ahmed SF, Deb S, Paul I, Chatterjee A, Mandal T, Chatterjee U, Ghosh MK. The Chaperone-assisted E3 Ligase C Terminus of Hsc70-interacting Protein (CHIP) Targets PTEN for Proteasomal Degradation. Journal of Biological Chemistry. 2012 May;287(19):15996–6006. doi: 10.1074/jbc.m111.321083.; Tay Y, Kats L, Salmena L, Weiss D, Tan SM, Ala U, Karreth F, Poliseno L, Provero P, Di Cunto F, Lieberman J, Rigoutsos I, Pandolfi PP. Coding-independent regulation of the tumor suppressor PTEN by competing endogenous mRNAs. Cell. 2011 Oct 14;147(2):344–57. PMID: 22000013; PMCID: PMC3235920.; Maddika S, Kavela S, Rani N, Palicharla VR, Pokorny JL, Sarkaria JN, Chen J. WWP2 is an E3 ubiquitin ligase for PTEN. Nat Cell Biol. 2011 Jun;13(6):728–33. PMID: 21532586; PMCID: PMC3926303.; Yoshimi A, Goyama S, Watanabe-Okochi N, Yoshiki Y, Nannya Y, Nitta E, Arai S, Sato T, Shimabe M, Nakagawa M, Imai Y, Kitamura T, Kurokawa M. Evi1 represses PTEN expression and activates PI3K/AKT/mTOR via interactions with polycomb proteins. Blood. 2011 Mar 30;117(13):3617–28. doi: 10.1182/blood-2009-12-261602. PMID: 21289308.; Poliseno L, Salmena L, Zhang J, Carver B, Haveman WJ, Pandolfi PP. A coding-independent function of gene and pseudogene mRNAs regulates tumour biology. Nature. 2010 Jun 24;465(7301):1033–8. PMID: 20577206; PMCID: PMC3206313.; Poliseno L, Salmena L, Riccardi L, Fornari A, Song MS, Hobbs RM, Sportoletti P, Varmeh S, Egia A, Fedele G, Rameh L, Loda M, Pandolfi PP. Identification of the miR-106b ~ 25 MicroRNA Cluster as a Proto-Oncogenic PTEN -Targeting Intron That Cooperates with Its Host Gene MCM7 in Transformation. Sci. Signal. 2010 Apr 13;3(117). doi: 10.1126/scisignal.2000594.; Kim H, Huang W, Jiang X, Pennicooke B, Park PJ, Johnson MD. Integrative genome analysis reveals an oncomir/oncogene cluster regulating glioblastoma survivorship. Proc Natl Acad Sci U S A. 2010 Feb 02;107(5):2183–8. PMID: 20080666; PMCID: PMC2836668.; Song LB, Li J, Liao WT, Feng Y, Yu CP, Hu LJ, Kong QL, Xu LH, Zhang X, Liu WL, Li MZ, Zhang L, Kang TB, Fu LW, Huang WL, Xia YF, Tsao SW, Li M, Band V, Band H, Shi QH, Zeng YX, Zeng MS. The polycomb group protein Bmi-1 represses the tumor suppressor PTEN and induces epithelial-mesenchymal transition in human nasopharyngeal epithelial cells. J Clin Invest. 2009 Dec;119(12):3626–36. PMID: 19884659; PMCID: PMC2786794.; Fine B, Hodakoski C, Koujak S, Su T, Saal LH, Maurer M, Hopkins B, Keniry M, Sulis ML, Mense S, Hibshoosh H, Parsons R. Activation of the PI3K pathway in cancer through inhibition of PTEN by exchange factor P-REX2a. Science. 2009 Sep 04;325(5945):1261–5. PMID: 19729658; PMCID: PMC2936784.; Van Themsche C, Leblanc V, Parent S, Asselin E. X-linked Inhibitor of Apoptosis Protein (XIAP) Regulates PTEN Ubiquitination, Content, and Compartmentalization. Journal of Biological Chemistry. 2009 Jul;284(31):20462–6. doi: 10.1074/jbc.c109.009522.; Huse JT, Brennan C, Hambardzumyan D, Wee B, Pena J, Rouhanifard SH, Sohn-Lee C, le Sage C, Agami R, Tuschl T, Holland EC. The PTEN-regulating microRNA miR-26a is amplified in high-grade glioma and facilitates gliomagenesis in vivo. Genes Dev. 2009 Jun 01;23(11):1327–37. PMID: 19487573; PMCID: PMC2701585.; Lu J, Jeong H, Kong N, Yang Y, Carroll J, Luo HR, Silberstein LE, YupoMa, Chai L. Correction: Stem Cell Factor SALL4 Represses the Transcriptions of PTEN and SALL1 through an Epigenetic Repressor Complex. PLoS ONE. 2009 Jul 27;4(7). doi: 10.1371/annotation/e0bd3a57-1ce4-4eaf-83de-034d39cac787.; Yim EK, Peng G, Dai H, Hu R, Li K, Lu Y, Mills GB, Meric-Bernstam F, Hennessy BT, Craven RJ, Lin SY. Rak functions as a tumor suppressor by regulating PTEN protein stability and function. Cancer Cell. 2009 Apr 07;15(4):304–14. PMID: 19345329; PMCID: PMC2673492.; Ikenoue T, Inoki K, Zhao B, Guan KL. PTEN acetylation modulates its interaction with PDZ domain. Cancer Res. 2008 Sep 01;68(17):6908–12. doi: 10.1158/0008-5472.can-08-1107. PMID: 18757404.; Song MS, Salmena L, Carracedo A, Egia A, Lo-Coco F, Teruya-Feldstein J, Pandolfi PP. The deubiquitinylation and localization of PTEN are regulated by a HAUSP-PML network. Nature. 2008 Oct 09;455(7214):813–7. PMID: 18716620; PMCID: PMC3398484.; Yang J, Chai L, Gao C, Fowles TC, Alipio Z, Dang H, Xu D, Fink LM, Ward DC, Ma Y. SALL4 is a key regulator of survival and apoptosis in human leukemic cells. Blood. 2008 Aug 01;112(3):805–13. PMID: 18487508; PMCID: PMC2481537.; Xiao C, Srinivasan L, Calado DP, Patterson HC, Zhang B, Wang J, Henderson JM, Kutok JL, Rajewsky K. Lymphoproliferative disease and autoimmunity in mice with increased miR-17-92 expression in lymphocytes. Nat Immunol. 2008 Apr;9(4):405–14. PMID: 18327259; PMCID: PMC2533767.; Escrivà M, Peiró S, Herranz N, Villagrasa P, Dave N, Montserrat-Sentís B, Murray SA, Francí C, Gridley T, Virtanen I, García de Herreros A. Repression of PTEN Phosphatase by Snail1 Transcriptional Factor during Gamma Radiation-Induced Apoptosis. Molecular and Cellular Biology. 2008 Mar 01;28(5):1528–40. doi: 10.1128/mcb.02061-07.; Yang H, Kong W, He L, Zhao JJ, O'Donnell JD, Wang J, Wenham RM, Coppola D, Kruk PA, Nicosia SV, Cheng JQ. MicroRNA expression profiling in human ovarian cancer: miR-214 induces cell survival and cisplatin resistance by targeting PTEN. Cancer Res. 2008 Jan 15;68(2):425–33. doi: 10.1158/0008-5472.can-07-2488. PMID: 18199536.; Vasudevan KM, Burikhanov R, Goswami A, Rangnekar VM. Suppression of PTEN expression is essential for antiapoptosis and cellular transformation by oncogenic Ras. Cancer Res. 2007 Nov 01;67(21):10343–50. doi: 10.1158/0008-5472.can-07-1827. PMID: 17974977.; Meng F, Henson R, Wehbe–Janek H, Ghoshal K, Jacob ST, Patel T. MicroRNA-21 Regulates Expression of the PTEN Tumor Suppressor Gene in Human Hepatocellular Cancer. Gastroenterology. 2007 Aug;133(2):647–58. doi: 10.1053/j.gastro.2007.05.022.; Wang X, Trotman LC, Koppie T, Alimonti A, Chen Z, Gao Z, Wang J, Erdjument-Bromage H, Tempst P, Cordon-Cardo C, Pandolfi PP, Jiang X. NEDD4-1 is a proto-oncogenic ubiquitin ligase for PTEN. Cell. 2007 Jan 12;128(1):129–39. PMID: 17218260; PMCID: PMC1828909.; Trotman LC, Wang X, Alimonti A, Chen Z, Teruya-Feldstein J, Yang H, Pavletich NP, Carver BS, Cordon-Cardo C, Erdjument-Bromage H, Tempst P, Chi SG, Kim HJ, Misteli T, Jiang X, Pandolfi PP. Ubiquitination regulates PTEN nuclear import and tumor suppression. Cell. 2007 Jan 12;128(1):141–56. PMID: 17218261; PMCID: PMC1855245.; Okumura K, Mendoza M, Bachoo RM, DePinho RA, Cavenee WK, Furnari FB. PCAF Modulates PTEN Activity. Journal of Biological Chemistry. 2006 Sep;281(36):26562–8. doi: 10.1074/jbc.m605391200.; Zhang CL, Zou Y, Yu RT, Gage FH, Evans RM. Nuclear receptor TLX prevents retinal dystrophy and recruits the corepressor atrophin1. Genes Dev. 2006 May 15;20(10):1308–20. PMID: 16702404; PMCID: PMC1472905.; Shen YH, Zhang L, Gan Y, Wang X, Wang J, LeMaire SA, Coselli JS, Wang XL. Up-regulation of PTEN (phosphatase and tensin homolog deleted on chromosome ten) mediates p38 MAPK stress signal-induced inhibition of insulin signaling. A cross-talk between stress signaling and insulin signaling in resistin-treated human endothelial cells. J Biol Chem. 2006 Mar 24;281(12):7727–36. doi: 10.1074/jbc.m511105200. PMID: 16418168.; Miller SJ, Lou DY, Seldin DC, Lane WS, Neel BG. Direct identification of PTEN phosphorylation sites. FEBS Lett. 2002 Sep 25;528(1-3):145–53. doi: 10.1016/s0014-5793(02)03274-x. PMID: 12297295.; Virolle T, Adamson ED, Baron V, Birle D, Mercola D, Mustelin T, de Belle I. The Egr-1 transcription factor directly activates PTEN during irradiation-induced signalling. Nat Cell Biol. 2001 Dec;3(12):1124–8. doi: 10.1038/ncb1201-1124. PMID: 11781575.; Stambolic V, MacPherson D, Sas D, Lin Y, Snow B, Jang Y, Benchimol S, Mak TW. Regulation of PTEN transcription by p53. Mol Cell. 2001 Aug;8(2):317–25. doi: 10.1016/s1097-2765(01)00323-9. PMID: 11545734.; Patel L, Pass I, Coxon P, Downes CP, Smith SA, Macphee CH. Tumor suppressor and anti-inflammatory actions of PPARgamma agonists are mediated via upregulation of PTEN. Curr Biol. 2001 May 15;11(10):764–8. doi: 10.1016/s0960-9822(01)00225-1. PMID: 11378386.; Torres J, Pulido R. The tumor suppressor PTEN is phosphorylated by the protein kinase CK2 at its C terminus. Implications for PTEN stability to proteasome-mediated degradation. J Biol Chem. 2001 Jan 12;276(2):993–8. doi: 10.1074/jbc.m009134200. PMID: 11035045.

Metabolites

H2O

Formula: H2O (18.0105642)

CAS ID: 7732-18-5

Nicotinamide

Formula: C6H6N2O (122.0480106)

CAS ID: 98-92-0

ATP(4-)

Formula: C10H12N5O13P3 (502.9644492)

CAS ID:

GTP(4-)

Formula: C10H12N5O14P3 (518.9593642)

CAS ID: 86527-72-2

NAD(1-)

Formula: C21H26N7O14P2 (662.1012936000001)

CAS ID: 53-84-9

ADP(3-)

Formula: C10H12N5O10P2 (424.0059412)

CAS ID:



Enzyme

EC Number name full name note
2.3.2.-
2.1.1.356 [histone H3]-lysine27 N-trimethyltransferase S-adenosyl-L-methionine:[histone H3]-L-lysine27 N6-methyltransferase
2.1.1.367 [histone H3]-lysine9 N-methyltransferase S-adenosyl-L-methionine:[histone H3]-L-lysine9 N6-methyltransferase
2.3.2.27 RING-type E3 ubiquitin transferase [E2 ubiquitin-conjugating enzyme]-S-ubiquitinyl-L-cysteine:[acceptor protein] ubiquitin transferase (isopeptide bond-forming; RING-type)
2.7.10.2 non-specific protein-tyrosine kinase ATP:[protein]-L-tyrosine O-phosphotransferase (non-specific)
2.7.11.24 mitogen-activated protein kinase ATP:protein phosphotransferase (MAPKK-activated)
3.1.3.16 protein-serine/threonine phosphatase protein-serine/threonine-phosphate phosphohydrolase
3.1.3.48 protein-tyrosine-phosphatase protein-tyrosine-phosphate phosphohydrolase
3.1.3.67 phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase 1-phosphatidyl-1D-myo-inositol-3,4,5-trisphosphate 3-phosphohydrolase
3.4.19.12 ubiquitinyl hydrolase 1
3.5.1.98 histone deacetylase histone amidohydrolase
3.6.4.13 RNA helicase


Proteins

Protein ID name full name