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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2016-02-02

AUTHORS

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

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. More... »

PAGES

15044

References to SciGraph publications

  • 2009-05-13. Physiological functions of the HECT family of ubiquitin ligases in NATURE REVIEWS MOLECULAR CELL BIOLOGY
  • 2013-05-14. Regulation of APCCdh1 E3 ligase activity by the Fbw7/cyclin E signaling axis contributes to the tumor suppressor function of Fbw7 in CELL RESEARCH
  • 2011-05-01. WWP2 is an E3 ubiquitin ligase for PTEN in NATURE CELL BIOLOGY
  • 2008-06. Deregulated proteolysis by the F-box proteins SKP2 and β-TrCP: tipping the scales of cancer in NATURE REVIEWS CANCER
  • 2006-08-09. The anaphase promoting complex/cyclosome: a machine designed to destroy in NATURE REVIEWS MOLECULAR CELL BIOLOGY
  • 1999-10. Accumulation of cyclin B1 requires E2F and cyclin-A-dependent rearrangement of the anaphase-promoting complex in NATURE
  • 2006-06-28. Degradation of Id2 by the anaphase-promoting complex couples cell cycle exit and axonal growth in NATURE
  • 2009-12-08. Wwp2 mediates Oct4 ubiquitination and its own auto-ubiquitination in a dosage-dependent manner in CELL RESEARCH
  • 2011-06-02. Cubism and the cell cycle: the many faces of the APC/C in NATURE REVIEWS MOLECULAR CELL BIOLOGY
  • 2009-08. Targeting PI3K signalling in cancer: opportunities, challenges and limitations in NATURE REVIEWS CANCER
  • 2010-12-19. The E3 ubiquitin ligase Wwp2 regulates craniofacial development through monoubiquitination of Goosecoid in NATURE CELL BIOLOGY
  • 2011-01-24. Selective targeting of activating and inhibitory Smads by distinct WWP2 ubiquitin ligase isoforms differentially modulates TGFβ signalling and EMT in ONCOGENE
  • 2008-06-15. Genomic stability and tumour suppression by the APC/C cofactor Cdh1 in NATURE CELL BIOLOGY
  • 2009-10-12. The emerging role of APC/CCdh1 in controlling differentiation, genomic stability and tumor suppression in ONCOGENE
  • 2004-11-17. G1 cell-cycle control and cancer in NATURE
  • 2004-03. Degradation of the SCF component Skp2 in cell-cycle phase G1 by the anaphase-promoting complex in NATURE
  • Journal

    TITLE

    Cell Discovery

    ISSUE

    1

    VOLUME

    2

    Author Affiliations

  • 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.
  • Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School , Boston, MA, USA.
  • 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.
  • 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.
  • 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.
  • Cell Division and Cancer group, Spanish National Cancer Research Centre (CNIO) , Madrid, Spain.
  • 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.
  • State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences , Shanghai, China.
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/celldisc.2015.44

    DOI

    http://dx.doi.org/10.1038/celldisc.2015.44

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1008706983

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/27462441


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    22 schema:description 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.
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