WWP2 is an E3 ubiquitin ligase for PTEN

Abstract

PTEN, a lipid phosphatase, is one of the most frequently mutated tumour suppressors in human cancer. Several recent studies have highlighted the importance of ubiquitylation in regulating PTEN tumour-suppressor function, but the enzymatic machinery required for PTEN ubiquitylation is not clear. In this study, by using a tandem affinity-purification approach, we have identified WWP2 (also known as atrophin-1-interacting protein 2, AIP-2) as a PTEN-interacting protein. WWP2 is an E3 ubiquitin ligase that belongs to the NEDD4-like protein family, which is involved in regulating transcription, embryonic stem-cell fate, cellular transport and T-cell activation processes. We show that WWP2 physically interacts with PTEN and mediates its degradation through a ubiquitylation-dependent pathway. Functionally, we show that WWP2 controls cellular apoptosis and is required for tumorigenicity of cells. Collectively, our results reveal a functional E3 ubiquitin ligase for PTEN that plays a vital role in tumour-cell survival.

Cdh1, a Substrate-recruiting Component of Anaphase-promoting Complex/Cyclosome (APC/C) Ubiquitin E3 Ligase, Specifically Interacts with Phosphatase and Tensin Homolog (PTEN) and Promotes Its Removal from Chromatin

“…RFP-mediated ubiquitination affects neither PTEN stability nor subcellular localization but rather inhibits its phosphatase activity (18). WWP2 physically interacts with PTEN and mediates its degradation through the ubiquitination-depen- dent process (17). It would be of interest to determine whether WWP2 may mediate the degradation/removal of chromatinassociated PTEN.…”

RFP-mediated ubiquitination of PTEN modulates its effect on AKT activation

“…Previously, two E3 ubiquitin ligases were identified to regulate PTEN stability and localization, which resulted in the inhibition of PTEN-mediated dephosphorylation of PIP3 [21,22,24]. PTEN serves as a critical regulator of AKT by tightly controlling the response of AKT signaling triggered by insulin.…”

Ring Finger Protein 149 Is an E3 Ubiquitin Ligase Active on Wild-type v-Raf Murine Sarcoma Viral Oncogene Homolog B1 (BRAF)

“…Tandem Affinity Purification-Wild-type BRAF-associated proteins were isolated by using tandem affinity purification (11). Briefly, colon cancer cells that express endogenous wildtype BRAF were treated with simvastatin, and then the decreased level of wild-type BRAF was confirmed by Western blot analysis using anti-BRAF antibody.…”

“…The proteins bound to S-protein_ agarose beads were resolved by SDS-PAGE and visualized by Coomassie Blue staining. The identities of eluted proteins were revealed by mass spectrometry analysis (11).…”