Notch3 interactome analysis identified WWP2 as a negative regulator of Notch3 signaling in ovarian cancer.

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  • Additional Information
    • Source:
      Publisher: Public Library of Science Country of Publication: United States NLM ID: 101239074 Publication Model: eCollection Cited Medium: Internet ISSN: 1553-7404 (Electronic) Linking ISSN: 15537390 NLM ISO Abbreviation: PLoS Genet Subsets: MEDLINE
    • Publication Information:
      Original Publication: San Francisco, CA : Public Library of Science, c2005-
    • Subject Terms:
      Carcinogenesis*; Ovarian Neoplasms/*genetics ; Receptors, Notch/*biosynthesis ; Ubiquitin-Protein Ligases/*biosynthesis; Animals ; Cell Line, Tumor ; Epithelial Cells/metabolism ; Epithelial Cells/pathology ; Female ; Gene Expression Regulation, Developmental ; Humans ; Lysosomes ; Mice ; Ovarian Neoplasms/pathology ; Proteomics ; RNA, Small Interfering ; Receptor, Notch3 ; Receptors, Notch/genetics ; Signal Transduction ; Ubiquitin-Protein Ligases/genetics ; Xenograft Model Antitumor Assays
    • Abstract:
      The Notch3 signaling pathway is thought to play a critical role in cancer development, as evidenced by the Notch3 amplification and rearrangement observed in human cancers. However, the molecular mechanism by which Notch3 signaling contributes to tumorigenesis is largely unknown. In an effort to identify the molecular modulators of the Notch3 signaling pathway, we screened for Notch3-intracellular domain (N3-ICD) interacting proteins using a human proteome microarray. Pathway analysis of the Notch3 interactome demonstrated that ubiquitin C was the molecular hub of the top functional network, suggesting the involvement of ubiquitination in modulating Notch3 signaling. Thereby, we focused on functional characterization of an E3 ubiquitin-protein ligase, WWP2, a top candidate in the Notch3 interactome list. Co-immunoprecipitation experiments showed that WWP2 interacted with N3-ICD but not with intracellular domains from other Notch receptors. Wild-type WWP2 but not ligase-deficient mutant WWP2 increases mono-ubiquitination of the membrane-tethered Notch3 fragment, therefore attenuating Notch3 pathway activity in cancer cells and leading to cell cycle arrest. The mono-ubiquitination by WWP2 may target an endosomal/lysosomal degradation fate for Notch3 as suggested by the fact that the process could be suppressed by the endosomal/lysosomal inhibitor. Analysis of The Cancer Genome Atlas dataset showed that the majority of ovarian carcinomas harbored homozygous or heterozygous deletions in WWP2 locus, and there was an inverse correlation in the expression levels between WWP2 and Notch3 in ovarian carcinomas. Furthermore, ectopic expression of WWP2 decreased tumor development in a mouse xenograft model and suppressed the Notch3-induced phenotypes including increase in cancer stem cell-like cell population and platinum resistance. Taken together, our results provide evidence that WWP2 serves as a tumor suppressor by negatively regulating Notch3 signaling in ovarian cancer.
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    • Grant Information:
      R01 CA148826 United States CA NCI NIH HHS; R01CA148826 United States CA NCI NIH HHS; U24 CA160036 United States CA NCI NIH HHS; R01 CA103937 United States CA NCI NIH HHS; R01CA103937 United States CA NCI NIH HHS
    • Accession Number:
      0 (NOTCH3 protein, human)
      0 (RNA, Small Interfering)
      0 (Receptor, Notch3)
      0 (Receptors, Notch)
      EC 2.3.2.26 (WWP2 protein, human)
      EC 2.3.2.27 (Ubiquitin-Protein Ligases)
    • Publication Date:
      Date Created: 20141031 Date Completed: 20150630 Latest Revision: 20201217
    • Publication Date:
      20240829
    • Accession Number:
      PMC4214668
    • Accession Number:
      10.1371/journal.pgen.1004751
    • Accession Number:
      25356737