Reactome | PTEN Regulation

PTEN Regulation

Stable Identifier

R-HSA-6807070

DOI

10.3180/R-HSA-6807070.1

Type

Pathway

Species

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
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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
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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
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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