PTEN Regulation

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Homo sapiens
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PTEN is regulated at the level of gene transcription, mRNA translation, localization and protein stability.

Transcription of the PTEN gene is regulated at multiple levels. Epigenetic repression involves the recruitment of Mi-2/NuRD upon SALL4 binding to the PTEN promoter (Yang et al. 2008, Lu et al. 2009) or EVI1-mediated recruitment of the polycomb repressor complex (PRC) to the PTEN promoter (Song et al. 2009, Yoshimi et al. 2011). Transcriptional regulation is also elicited by negative regulators, including NR2E1:ATN1 (atrophin-1) complex, JUN (c-Jun), SNAIL and SLUG (Zhang et al. 2006, Vasudevan et al. 2007, Escriva et al. 2008, Uygur et al. 2015) and positive regulators such as TP53 (p53), MAF1, ATF2, EGR1 or PPARG (Stambolic et al. 2001, Virolle et al. 2001, Patel et al. 2001, Shen et al. 2006, Li et al. 2016).

MicroRNAs miR-26A1, miR-26A2, miR-22, miR-25, miR-302, miR-214, miR-17-5p, miR-19 and miR-205 bind PTEN mRNA and inhibit its translation into protein. These microRNAs are altered in cancer and can account for changes in PTEN levels (Meng et al. 2007, Xiao et al. 2008, Yang et al. 2008, Huse et al. 2009, Kim et al. 2010, Poliseno, Salmena, Riccardi et al. 2010, Cai et al. 2013). In addition, coding and non-coding RNAs can prevent microRNAs from binding to PTEN mRNA. These RNAs are termed competing endogenous RNAs or ceRNAs. Transcripts of the pseudogene PTENP1 and mRNAs transcribed from SERINC1, VAPA and CNOT6L genes exhibit this activity (Poliseno, Salmena, Zhang et al. 2010, Tay et al. 2011, Tay et al. 2014).

PTEN can translocate from the cytosol to the nucleus after undergoing monoubiquitination. PTEN's ability to localize to the nucleus contributes to its tumor suppressive role (Trotman et al. 2007). The ubiquitin protease USP7 (HAUSP) targets monoubiquitinated PTEN in the nucleus, resulting in PTEN deubiquitination and nuclear exclusion. PML, via an unknown mechanism that involves USP7- and PML-interacting protein DAXX, inhibits USP7-mediated deubiquitination of PTEN, thus promoting PTEN nuclear localization. Disruption of PML function in acute promyelocytic leukemia, through a chromosomal translocation that results in expression of a fusion protein PML-RARA, leads to aberrant PTEN localization (Song et al. 2008).

Several ubiquitin ligases, including NEDD4, WWP2, STUB1 (CHIP), RNF146, XIAP and MKRN1, polyubiquitinate PTEN and target it for proteasome-mediated degradation (Wang et al. 2007, Van Themsche et al. 2009, Ahmed et al. 2011, Maddika et al. 2011, Lee et al. 2015, Li et al. 2015). The ubiquitin proteases USP13 and OTUD3, frequently down-regulated in breast cancer, remove polyubiquitin chains from PTEN, thus preventing its degradation and increasing its half-life (Zhang et al. 2013, Yuan et al. 2015). The catalytic activity of PTEN is negatively regulated by PREX2 binding (Fine et al. 2009, Hodakoski et al. 2014) and TRIM27-mediated ubiquitination (Lee et al. 2013), most likely through altered PTEN conformation.

In addition to ubiquitination, PTEN also undergoes SUMOylation (Gonzalez-Santamaria et al. 2012, Da Silva Ferrada et al. 2013, Lang et al. 2015, Leslie et al. 2016). SUMOylation of the C2 domain of PTEN may regulate PTEN association with the plasma membrane (Shenoy et al. 2012) as well as nuclear localization of PTEN (Bassi et al. 2013, Collaud et al. 2016). PIASx-alpha, a splicing isorom of E3 SUMO-protein ligase PIAS2 has been implicated in PTEN SUMOylation (Wang et al. 2014). SUMOylation of PTEN may be regulated by activated AKT (Lin et al. 2016). Reactions describing PTEN SUMOylation will be annotated when mechanistic details become available.

Phosphorylation affects the stability and activity of PTEN. FRK tyrosine kinase (RAK) phosphorylates PTEN on tyrosine residue Y336, which increases PTEN half-life by inhibiting NEDD4-mediated polyubiquitination and subsequent degradation of PTEN. FRK-mediated phosphorylation also increases PTEN enzymatic activity (Yim et al. 2009). Casein kinase II (CK2) constitutively phosphorylates the C-terminal tail of PTEN on serine and threonine residues S370, S380, T382, T383 and S385. CK2-mediated phosphorylation increases PTEN protein stability (Torres and Pulido 2001) but results in ~30% reduction in PTEN lipid phosphatase activity (Miller et al. 2002).

PTEN localization and activity are affected by acetylation of its lysine residues (Okumura et al. 2006, Ikenoue et al. 2008, Meng et al. 2016). PTEN can undergo oxidation, which affects its function, but the mechanism is poorly understood (Tan et al. 2015, Shen et al. 2015, Verrastro et al. 2016).

Literature References
PubMed ID Title Journal Year
20388916 Identification of the miR-106b~25 microRNA cluster as a proto-oncogenic PTEN-targeting intron that cooperates with its host gene MCM7 in transformation

Rameh, L, Varmeh, S, Sportoletti, P, Fornari, A, Loda, M, Poliseno, L, Fedele, G, Song, MS, Riccardi, L, Hobbs, RM, Pandolfi, PP, Egia, A, Salmena, L

Sci Signal 2010
24367090 Regulation of PTEN inhibition by the pleckstrin homology domain of P-REX2 during insulin signaling and glucose homeostasis

Kern, PA, Keniry, M, Anderson, KE, Hawkins, PT, Mense, SM, Barrows, D, Stephens, LR, Parsons, R, Hodakoski, C, Hopkins, BD

Proc. Natl. Acad. Sci. U.S.A. 2014
25547115 Poly-ADP ribosylation of PTEN by tankyrases promotes PTEN degradation and tumor growth

Yang, L, Lin, C, Wang, W, Li, N, Chen, J, Songyang, Z, Feng, L, Zhang, Y, Liang, K, Wang, J, Yu, Y, Han, X

Genes Dev. 2015
18716620 The deubiquitinylation and localization of PTEN are regulated by a HAUSP-PML network

Pandolfi, PP, Carracedo, A, Egia, A, Song, MS, Teruya-Feldstein, J, Lo-Coco, F, Salmena, L

Nature 2008
16418168 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

Wang, J, Shen, YH, LeMaire, SA, Wang, XL, Coselli, JS, Gan, Y, Zhang, L, Wang, X

J. Biol. Chem. 2006
20080666 Integrative genome analysis reveals an oncomir/oncogene cluster regulating glioblastoma survivorship

Park, PJ, Johnson, MD, Jiang, X, Kim, H, Huang, W, Pennicooke, B

Proc. Natl. Acad. Sci. U.S.A. 2010
11781575 The Egr-1 transcription factor directly activates PTEN during irradiation-induced signalling

Baron, V, Virolle, T, Mustelin, T, Birle, D, Adamson, ED, de Belle, I, Mercola, D

Nat. Cell Biol. 2001
24429633 The multilayered complexity of ceRNA crosstalk and competition

Pandolfi, PP, Rinn, J, Tay, Y

Nature 2014
26280536 Deubiquitylase OTUD3 regulates PTEN stability and suppresses tumorigenesis

Lv, Y, Zhang, Y, Xiao, ZX, Song, S, Xing, G, Gao, H, Li, H, Zhou, T, Wei, W, Kong, X, Yin, Y, Wang, L, He, F, Gao, D, Li, Y, Yuan, L, Zhang, L

Nat. Cell Biol. 2015
11378386 Tumor suppressor and anti-inflammatory actions of PPARgamma agonists are mediated via upregulation of PTEN

Downes, CP, Patel, L, MacPhee, CH, Coxon, P, Pass, I, Smith, SA

Curr. Biol. 2001
11545734 Regulation of PTEN transcription by p53

Stambolic, V, Sas, D, Benchimol, S, Snow, B, Jang, Y, MacPherson, D, Lin, Y, Mak, TW

Mol. Cell 2001
18757404 PTEN acetylation modulates its interaction with PDZ domain

Guan, KL, Inoki, K, Ikenoue, T, Zhao, B

Cancer Res. 2008
19345329 Rak functions as a tumor suppressor by regulating PTEN protein stability and function

Li, K, Dai, H, Lu, Y, Hu, R, Craven, RJ, Hennessy, BT, Meric-Bernstam, F, Mills, GB, Yim, EK, Lin, SY, Peng, G

Cancer Cell 2009
26910647 MAF1 suppresses AKT-mTOR signaling and liver cancer through activation of PTEN transcription

Zheng, XF, Huang, W, Li, M, Fu, L, Li, XX, Wang, HY, Yang, Y, Li, Y, Wang, S, Tsang, CK

Hepatology 2016
19487573 The PTEN-regulating microRNA miR-26a is amplified in high-grade glioma and facilitates gliomagenesis in vivo

Rouhanifard, SH, le Sage, C, Hambardzumyan, D, Brennan, C, Holland, EC, Sohn-Lee, C, Pena, J, Agami, R, Huse, JT, Tuschl, T, Wee, B

Genes Dev. 2009
18327259 Lymphoproliferative disease and autoimmunity in mice with increased miR-17-92 expression in lymphocytes

Zhang, B, Xiao, C, Kutok, JL, Henderson, JM, Wang, J, Calado, DP, Srinivasan, L, Rajewsky, K, Patterson, HC

Nat. Immunol. 2008
26183061 PI3K/AKT activation induces PTEN ubiquitination and destabilization accelerating tumourigenesis

Hewitt, SM, Han, HJ, Lee, MS, Lee, C, Chung, JY, Kim, JH, Jeong, MH, Ko, A, Cho, H, Lee, HW, Song, J, Chun, KH

Nat Commun 2015
18199536 MicroRNA expression profiling in human ovarian cancer: miR-214 induces cell survival and cisplatin resistance by targeting PTEN

Kong, W, O'Donnell, JD, Kruk, PA, Zhao, JJ, He, L, Wenham, RM, Cheng, JQ, Nicosia, SV, Coppola, D, Wang, J, Yang, H

Cancer Res. 2008
26862215 The PTEN protein: cellular localization and post-translational regulation

Wise, HM, Hermida, MA, Kriplani, N, Alvarez-Garcia, V, Leslie, NR

Biochem. Soc. Trans. 2016
19440552 Stem cell factor SALL4 represses the transcriptions of PTEN and SALL1 through an epigenetic repressor complex

Jeong, HW, Silberstein, LE, Carroll, J, Chai, L, Yang, Y, Kong, N, Lu, J, Luo, HR, Yupoma, LE

PLoS One 2009
12297295 Direct identification of PTEN phosphorylation sites

Lane, WS, Miller, SJ, Seldin, DC, Neel, BG, Lou, DY

FEBS Lett. 2002
19729658 Activation of the PI3K pathway in cancer through inhibition of PTEN by exchange factor P-REX2a

Keniry, M, Koujak, S, Hibshoosh, H, Sulis, ML, Fine, B, Mense, S, Maurer, M, Saal, LH, Su, T, Parsons, R, Hodakoski, C, Hopkins, B

Science 2009
25224693 Analysis of PTEN ubiquitylation and SUMOylation using molecular traps

Lang, V, Xolalpa, W, Zabaleta, L, Aillet, F, Rivas, C, Rodriguez, MS, Da Silva-Ferrada, E

Methods 2015
25867063 SUMO modification of Akt regulates global SUMOylation and substrate SUMOylation specificity through Akt phosphorylation of Ubc9 and SUMO1

Lin, CH, Liu, SY, Lee, EH

Oncogene 2016
23013792 Regulation of the tumor suppressor PTEN by SUMO

Rivas, C, Ortega-Molina, A, Campagna, M, Esteban, M, González, D, Serrano, M, González-Santamaría, J, Marcos-Villar, L, Gallego, P, Rodriguez, MS, de la Cruz-Herrera, CF, Lopitz-Otsoa, F

Cell Death Dis 2012
11035045 The tumor suppressor PTEN is phosphorylated by the protein kinase CK2 at its C terminus. Implications for PTEN stability to proteasome-mediated degradation

Pulido, R, Torres, J

J. Biol. Chem. 2001
23604351 Analysis of SUMOylated proteins using SUMO-traps

Carracedo, A, Lopitz-Otsoa, F, Lang, V, Xolalpa, W, Aillet, F, de la Cruz-Herrera, CF, Rivas, C, Rodriguez, MS, Martin-Ruiz, I, Goldenberg, SJ, Da Silva-Ferrada, E, England, P

Sci Rep 2013
25884169 Lung neuroendocrine tumors: correlation of ubiquitinylation and sumoylation with nucleo-cytosolic partitioning of PTEN

Weder, W, Komminoth, P, Oehlschlegel, C, Soltermann, A, Atanassoff, A, Collaud, S, Wiedl, T, Tischler, V

BMC Cancer 2015
23888040 Nuclear PTEN controls DNA repair and sensitivity to genotoxic stress

Stambolic, V, Neel, BG, Raught, B, Miller, SJ, Bassi, C, Gorrini, C, Dowling, RJ, Srikumar, T, Mak, TW, Ho, J

Science 2013
21532586 WWP2 is an E3 ubiquitin ligase for PTEN

Pokorny, JL, Palicharla, VR, Kavela, S, Chen, J, Maddika, S, Rani, N, Sarkaria, JN

Nat. Cell Biol. 2011
23419514 RFP-mediated ubiquitination of PTEN modulates its effect on AKT activation

Gu, W, Zhou, B, Lee, JT, Zhong, J, Parsons, R, Zhou, A, Li, M, Shan, J

Cell Res. 2013
17218260 NEDD4-1 is a proto-oncogenic ubiquitin ligase for PTEN

Pandolfi, PP, Cordon-Cardo, C, Trotman, LC, Gao, Z, Wang, J, Chen, Z, Wang, X, Jiang, X, Koppie, T, Tempst, P, Alimonti, A, Erdjument-Bromage, H

Cell 2007
22427670 The chaperone-assisted E3 ligase C terminus of Hsc70-interacting protein (CHIP) targets PTEN for proteasomal degradation

Paul, I, Mandal, T, Chatterjee, U, Ahmed, SF, Ghosh, MK, Chatterjee, A, Deb, S

J. Biol. Chem. 2012
23073177 Membrane association of the PTEN tumor suppressor: electrostatic interaction with phosphatidylserine-containing bilayers and regulatory role of the C-terminal tail

Shenoy, SS, Lösche, M, Nanda, H

J. Struct. Biol. 2012
18487508 SALL4 is a key regulator of survival and apoptosis in human leukemic cells

Ma, Y, Alipio, Z, Ward, DC, Xu, D, Dang, H, Gao, C, Yang, J, Chai, L, Fowles, TC, Fink, LM

Blood 2008
17681183 MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer

Wehbe-Janek, H, Patel, T, Meng, F, Henson, R, Jacob, ST, Ghoshal, K

Gastroenterology 2007
17218261 Ubiquitination regulates PTEN nuclear import and tumor suppression

Trotman, LC, Wang, X, Carver, BS, Jiang, X, Pavletich, NP, Tempst, P, Erdjument-Bromage, H, Teruya-Feldstein, J, Pandolfi, PP, Misteli, T, Cordon-Cardo, C, Chen, Z, Kim, HJ, Chi, SG, Yang, H, Alimonti, A

Cell 2007
19473982 X-linked inhibitor of apoptosis protein (XIAP) regulates PTEN ubiquitination, content, and compartmentalization

Van Themsche, C, Parent, S, Leblanc, V, Asselin, E

J. Biol. Chem. 2009
21289308 Evi1 represses PTEN expression and activates PI3K/AKT/mTOR via interactions with polycomb proteins

Sato, T, Nitta, E, Kitamura, T, Yoshimi, A, Shimabe, M, Yoshiki, Y, Goyama, S, Arai, S, Nannya, Y, Kurokawa, M, Nakagawa, M, Imai, Y, Watanabe-Okochi, N

Blood 2011
24270891 Deubiquitylation and stabilization of PTEN by USP13

Ma, L, Wang, W, Chen, D, Chen, J, Sun, Y, Wang, M, Maddika, S, Piao, HL, Hung, MC, Wei, Y, Zhang, P, Zhang, J

Nat. Cell Biol. 2013
19884659 The polycomb group protein Bmi-1 represses the tumor suppressor PTEN and induces epithelial-mesenchymal transition in human nasopharyngeal epithelial cells

Huang, WL, Li, J, Feng, Y, Xia, YF, Shi, QH, Tsao, SW, Liu, WL, Zeng, YX, Yu, CP, Li, M, Kang, TB, Song, LB, Band, V, Zeng, MS, Band, H, Liao, WT, Kong, QL, Zhang, L, Li, MZ, Fu, LW, Zhang, X, Xu, LH, Hu, LJ

J. Clin. Invest. 2009
26415504 AIF inhibits tumor metastasis by protecting PTEN from oxidation

Shen, SM, Zhao, XY, Yu, Y, Zhang, FF, Xiong, Z, Chen, GQ, Guo, M

EMBO Rep. 2015
16702404 Nuclear receptor TLX prevents retinal dystrophy and recruits the corepressor atrophin1

Zhang, CL, Zou, Y, Gage, FH, Evans, RM, Yu, RT

Genes Dev. 2006
18172008 Repression of PTEN phosphatase by Snail1 transcriptional factor during gamma radiation-induced apoptosis

Gridley, T, Murray, SA, García de Herreros, A, Herranz, N, Dave, N, Virtanen, I, Peiró, S, Montserrat-Sentís, B, Escrivà, M, Villagrasa, P, Francí, C

Mol. Cell. Biol. 2008
25737250 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

Tan, PL, Shavlakadze, T, Grounds, MD, Arthur, PG

Int. J. Biochem. Cell Biol. 2015
24344134 PIASxα ligase enhances SUMO1 modification of PTEN protein as a SUMO E3 ligase

Cao, Z, Zhang, X, Tong, T, Wang, W, Chen, Y, Wang, S, Wang, W, Hu, N

J. Biol. Chem. 2014
26279303 PTEN activation through K163 acetylation by inhibiting HDAC6 contributes to tumour inhibition

Gan, YH, Meng, Z, Jia, LF

Oncogene 2016
16829519 PCAF modulates PTEN activity

Mendoza, M, DePinho, RA, Okumura, K, Furnari, FB, Cavenee, WK, Bachoo, RM

J. Biol. Chem. 2006
23856247 miR-205 targets PTEN and PHLPP2 to augment AKT signaling and drive malignant phenotypes in non-small cell lung cancer

Cai, J, Huang, Y, Li, R, Yang, Y, Yuan, J, Fang, L, Li, M, Chen, B, Zhu, X, Wu, J

Cancer Res. 2013
17974977 Suppression of PTEN expression is essential for antiapoptosis and cellular transformation by oncogenic Ras

Burikhanov, R, Vasudevan, KM, Goswami, A, Rangnekar, VM

Cancer Res. 2007
20577206 A coding-independent function of gene and pseudogene mRNAs regulates tumour biology

Pandolfi, PP, Carver, B, Haveman, WJ, Poliseno, L, Zhang, J, Salmena, L

Nature 2010
26561776 Reversible oxidation of phosphatase and tensin homolog (PTEN) alters its interactions with signaling and regulatory proteins

Verrastro, I, Spickett, CM, Woscholski, R, Tveen-Jensen, K, Pitt, AR

Free Radic. Biol. Med. 2016
25728608 SLUG is a direct transcriptional repressor of PTEN tumor suppressor

Liaw, L, Leikina, E, Wu, WS, Vary, C, Abramo, K, Uygur, B

Prostate 2015
22000013 Coding-independent regulation of the tumor suppressor PTEN by competing endogenous mRNAs

Weiss, D, Karreth, F, Tan, SM, Di Cunto, F, Rigoutsos, I, Provero, P, Ala, U, Kats, L, Poliseno, L, Tay, Y, Pandolfi, PP, Lieberman, J, Salmena, L

Cell 2011
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