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

Abstract

The PTEN tumor suppressor is a lipid phosphatase that has a central role in regulating the phosphatidylinositol-3-kinase (PI3K) signal transduction cascade. Nevertheless, the mechanism by which the PTEN activity is regulated in cells needs further elucidation. Although previous studies have shown that ubiquitination of PTEN can modulate its stability and subcellular localization, the role of ubiquitination in the most critical aspect of PTEN function, its phosphatase activity, has not been fully addressed. Here, we identify a novel E3 ubiquitin ligase of PTEN, Ret finger protein (RFP), that is able to promote atypical polyubiquitinations of PTEN. These ubiquitinations do not lead to PTEN instability or relocalization, but rather significantly inhibit PTEN phosphatase activity and therefore modulate its ability to regulate the PI3K signal transduction cascade. Indeed, RFP overexpression relieves PTEN-mediated inhibitory effects on AKT activation; in contrast, RNAi-mediated knockdown of endogenous RFP enhances the ability of PTEN to suppress AKT activation. Moreover, RFP-mediated ubiquitination of PTEN inhibits PTEN-dependent activation of TRAIL expression and also suppresses its ability to induce apoptosis. Our findings demonstrate a crucial role of RFP-mediated ubiquitination in controlling PTEN activity.

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).…”

“…NEDD4-1, WWP2, and RFP are three reported ubiquitin E3 ligases that mediate PTEN ubiquitination (16 -18). NEDD4-1 appears to be dispensable for regulation of PTEN subcellular localization and stability (19) whereas RFP functions to regulate its enzymatic activity (18). Cdh1 is a substrate-specific activator of anaphase-promoting complex/cyclosome (APC/C), an E3 ubiquitin ligase that targets specific substrates for degradation by the 26S proteasome during the cell cycle.…”

Plk1 Phosphorylation of PTEN Causes a Tumor-Promoting Metabolic State

“…We understand that PTEN regulation is exceedingly complex (33). Three E3 ubiquitin ligases, Nedd4-1, WWP2, and RFP, have been reported to mediate PTEN ubiquitination (34)(35)(36). We therefore tested the possibility that Plk1 also affects PTEN function via its activity toward these E3 ligases.…”

Identification of TRIM27 as a Novel Degradation Target of Herpes Simplex Virus 1 ICP0

“…Ubiquitination by TRIM27 modulates the activity of a given substrate rather than inducing its proteasomal degradation with the exception of NOD2 which it degrades (21). Ubiquitination by TRIM27 reduces the activity of PIK3C2B in T cells (22), inhibits PTEN to activate AKT1 (23), modifies WASH1 of the WASH regulatory complex to facilitate actin polymerization (24), and upregulates USP7-dependent deubiquitination of RIPK1 in tumor necrosis factor (TNF)-dependent apoptosis (25). We report here that TRIM27 is a novel degradation target of ICP0 during HSV-1 infection, and we characterize its role in the infected cell.…”