Reactome | Regulation of PTEN stability and activity

Regulation of PTEN stability and activity

Stable Identifier

R-HSA-8948751

Type

Pathway

Species

Homo sapiens

ReviewStatus

5/5

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Regulation of PTEN stability and activity

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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
19473982	X-linked inhibitor of apoptosis protein (XIAP) regulates PTEN ubiquitination, content, and compartmentalization Van Themsche, C, Leblanc, V, Parent, S, Asselin, E	J. Biol. Chem.	2009
19345329	Rak functions as a tumor suppressor by regulating PTEN protein stability and function Yim, EK, Peng, G, Dai, H, Hu, R, Li, K, Lu, Y, Mills, GB, Meric-Bernstam, F, Hennessy, BT, Craven, RJ, Lin, SY	Cancer Cell	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 Torres, J, Pulido, R	J. Biol. Chem.	2001
21532586	WWP2 is an E3 ubiquitin ligase for PTEN Maddika, S, Kavela, S, Rani, N, Palicharla, VR, Pokorny, JL, Sarkaria, JN, Chen, J	Nat. Cell Biol.	2011
26183061	PI3K/AKT activation induces PTEN ubiquitination and destabilization accelerating tumourigenesis Lee, MS, Jeong, MH, Lee, HW, Han, HJ, Ko, A, Hewitt, SM, Kim, JH, Chun, KH, Chung, JY, Lee, C, Cho, H, Song, J	Nat Commun	2015
24367090	Regulation of PTEN inhibition by the pleckstrin homology domain of P-REX2 during insulin signaling and glucose homeostasis Hodakoski, C, Hopkins, BD, Barrows, D, Mense, SM, Keniry, M, Anderson, KE, Kern, PA, Hawkins, PT, Stephens, LR, Parsons, R	Proc. Natl. Acad. Sci. U.S.A.	2014
22427670	The chaperone-assisted E3 ligase C terminus of Hsc70-interacting protein (CHIP) targets PTEN for proteasomal degradation Ahmed, SF, Deb, S, Paul, I, Chatterjee, A, Mandal, T, Chatterjee, U, Ghosh, MK	J. Biol. Chem.	2012
17218260	NEDD4-1 is a proto-oncogenic ubiquitin ligase for PTEN 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	Cell	2007
25547115	Poly-ADP ribosylation of PTEN by tankyrases promotes PTEN degradation and tumor growth Li, N, Zhang, Y, Han, X, Liang, K, Wang, J, Feng, L, Wang, W, Songyang, Z, Lin, C, Yang, L, Yu, Y, Chen, J	Genes Dev.	2015
19729658	Activation of the PI3K pathway in cancer through inhibition of PTEN by exchange factor P-REX2a Fine, B, Hodakoski, C, Koujak, S, Su, T, Saal, LH, Maurer, M, Hopkins, B, Keniry, M, Sulis, ML, Mense, S, Hibshoosh, H, Parsons, R	Science	2009
12297295	Direct identification of PTEN phosphorylation sites Miller, SJ, Lou, DY, Seldin, DC, Lane, WS, Neel, BG	FEBS Lett.	2002