Reactome | PTEN Regulation

PTEN Regulation

Stable Identifier

R-HSA-6807070

DOI

10.3180/R-HSA-6807070.1

Type

Pathway

Species

Homo sapiens

ReviewStatus

5/5

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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
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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
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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
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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
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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
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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