Cdh1 inhibits WWP2-mediated ubiquitination of PTEN to suppress tumorigenesis in an APC-independent manner.

Jianfeng Guo,Jiankang Liu,Jia Liu,Zhu Yuan,Wenyi Wei,Weiguo Zou,Marcos Malumbres,Jing Liu,Jinfang Zhang,Lixin Wan

doi:10.1038/celldisc.2015.44

Abstract

Anaphase-promoting complex/cyclosome/Cdh1 is a multi-subunit ubiquitin E3 ligase that drives M to G1 cell cycle progression through primarily earmarking various substrates for ubiquitination and subsequent degradation by the 26S proteasome. Notably, emerging evidence suggested that Cdh1 could also function in various cellular processes independent of anaphase-promoting complex/cyclosome. To this end, we recently identified an anaphase-promoting complex/cyclosome-independent function of Cdh1 in modulating osteoblast differentiation through activating Smurf1, one of the NEDD4 family of HECT domain-containing E3 ligases. However, it remains largely unknown whether Cdh1 could exert its tumor suppressor role through similarly modulating the E3 ligase activities of other NEDD4 family members, most of which have characterized important roles in tumorigenesis. Here we report that in various tumor cells, Cdh1, conversely, suppresses the E3 ligase activity of WWP2, another NEDD4 family protein, in an anaphase-promoting complex/cyclosome-independent manner. As such, loss of Cdh1 activates WWP2, leading to reduced abundance of WWP2 substrates including PTEN, which subsequently activates PI3K/Akt oncogenic signaling to facilitate tumorigenesis. This study expands the non-anaphase-promoting complex/cyclosome function of Cdh1 in regulating the NEDD4 family E3 ligases, and further suggested that enhancing Cdh1 to inhibit the E3 ligase activity of WWP2 could be a promising strategy for treating human cancers.

Highlights

The anaphase-promoting complex/cyclosome (APC/ C, named APC) is a 1.5-megadalton ubiquitin E3As one of the nine NEDD4 family of E3 ligase proteins, WWP2 contains an N-terminal membrane targeting C2 domain, four internal double tryptophan (WW) domains and a C-terminal HECT domain that confers E3 ligase activity [17]
To further investigate whether Cdh1 could control the E3 ligase activity of these Cdh1-interacting NEDD4 family of E3 ligases, we depleted endogenous Cdh1 in multiple cancer cell lines (Figure 1b and c and Supplementary Figure S1a and c) and examined the protein levels of NEDD4 family members interacting with Cdh1
As Cdh1 protein abundance fluctuates across cell cycle [3], we examined whether WWP2 abundance changes during cell cycle progression

Summary

Introduction

The anaphase-promoting complex/cyclosome (APC/ C, named APC) is a 1.5-megadalton ubiquitin E3As one of the nine NEDD4 family of E3 ligase proteins, WWP2 contains an N-terminal membrane targeting C2 domain, four internal double tryptophan (WW) domains and a C-terminal HECT domain that confers E3 ligase activity [17]. Similar to Smurf, the N-terminal C2 domain of WWP2 may interact with the C-terminal HECT domain within the same molecule, which forms a closed conformation to either block the access of substrates to the WW domain, or prevent E2 recruitment [17], leading to auto-suppression of its E3 ligase activity. Releasing this auto-suppression could lead to activation of various members of the NEDD4 family of E3 ligases. It remains largely uncharacterized whether a similar autosuppressive mechanism operates to govern the WWP2 E3 ligase activity and how WWP2 E3 ligase activity is regulated by upstream factors

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Results

Conclusion