title: Cdh1 inhibits WWP2-mediated ubiquitination of PTEN to suppress tumorigenesis in an APC-independent manner.
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.
authors.affiliation: Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Life Science, FIST, Xi'an Jiaotong University, Xi'an, China; Cardiovascular Research Center, Xi'an Jiaotong University School of Medicine, Xi'an, China; Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School , Boston, MA, USA.
authors.forename: Lixin
authors.initials: L
authors.lastname: Wan
authors.affiliation: Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Life Science, FIST, Xi'an Jiaotong University, Xi'an, China; Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; State Key Laboratory of Biotherapy and Cancer Center, Sichuan University/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Zhu
authors.initials: Z
authors.lastname: Yuan
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School , Boston, MA, USA.
authors.forename: Jinfang
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Guo
authors.affiliation: Cell Division and Cancer group, Spanish National Cancer Research Centre (CNIO) , Madrid, Spain.
authors.forename: Marcos
authors.initials: M
authors.lastname: Malumbres
authors.affiliation: Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Life Science, FIST, Xi'an Jiaotong University , Xi'an, China.
authors.forename: Jiankang
authors.initials: J
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences , Shanghai, China.
authors.forename: Weiguo
authors.initials: W
authors.lastname: Zou
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School , Boston, MA, USA.
authors.forename: Wenyi
authors.initials: W
authors.lastname: Wei
keywords: Akt; Cdh1; PTEN; WWP2; tumorigenesis