Regulation of PTEN stability and activity

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R-HSA-8948751
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Pathway
Species
Homo sapiens
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PTEN protein stability is regulated by ubiquitin ligases, such as NEDD4, WWP2, STUB1 (CHIP), XIAP, MKRN1 and RNF146, which polyubiquitinate PTEN in response to different stimuli and thus target it for proteasome-mediated degradation (Wang et al. 2007, Van Themsche et al. 2009, Maddika et al. 2011, Ahmed et al. 2012, Lee et al. 2015, Li et al. 2015). Several ubiquitin proteases, such as USP13 and OTUD3, can remove polyubiquitin chains from PTEN and rescue it from degradation (Zhang et al. 2013, Yuan et al. 2015). TRIM27 (RFP) is an E3 ubiquitin ligase that polyubiquitinates PTEN on multiple lysines in the C2 domain of PTEN using K27 linkage between ubiquitin molecules. TRIM27 mediated ubiquitination inhibits PTEN lipid phosphatase activity, but does not affect PTEN protein localization or stability (Lee et al. 2013).
PTEN phosphorylation by the tyrosine kinase FRK (RAK) inhibits NEDD4 mediated polyubiquitination and subsequent degradation of PTEN, thus increasing PTEN half life. FRK mediated phosphorylation also increases PTEN enzymatic activity (Yim et al. 2009). Casein kinase 2 (CK2) mediated phosphorylation of the C-terminus of PTEN on multiple serine and threonine residues increases PTEN protein stability (Torres and Pulido 2001) but results in ~30% reduction in PTEN lipid phosphatase activity (Miller et al. 2002).
PREX2, a RAC1 guanine nucleotide exchange factor (GEF) can binds to PTEN and inhibit its catalytic activity (Fine et al. 2009).

Literature References
PubMed ID Title Journal Year
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
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
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
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
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
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
12297295 Direct identification of PTEN phosphorylation sites

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

FEBS Lett. 2002
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
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
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
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
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