title: DUB3 Deubiquitylating Enzymes Regulate Hippo Pathway Activity by Regulating the Stability of ITCH, LATS and AMOT Proteins.
abstract: The YAP and TAZ transcriptional coactivators promote oncogenic transformation. Elevated YAP/TAZ activity has been documented in human tumors. YAP and TAZ are negatively regulated by the Hippo tumor suppressor pathway. The activity and stability of several Hippo pathway components, including YAP/TAZ, is regulated by ubiquitin mediated protein turnover and several ubiquitin ligase complexes have been implicated in human cancer. However, little is known about the deubiquitylating enzymes that counteract these ubiquitin ligases in regulation of the Hippo pathway. Here we identify the DUB3 family deubiquitylating enzymes as regulators of Hippo pathway activity. We provide evidence that DUB3 proteins regulate YAP/TAZ activity by controlling the stability of the E3 ligase ITCH, the LATS kinases and the AMOT family proteins. As a novel Hippo pathway regulator, DUB3 has the potential to act a tumor suppressor by limiting YAP activity.
authors.affiliation: Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Hung Thanh
authors.initials: HT
authors.lastname: Nguyen
authors.affiliation: Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jan-Michael
authors.initials: JM
authors.lastname: Kugler
authors.affiliation: Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Stephen M
authors.identifier: http://orcid.org/0000-0003-2858-9163
authors.initials: SM
authors.lastname: Cohen
mesh_terms: D000091082:Angiomotins; D000818:Animals; D018797:Cell Cycle Proteins; D002460:Cell Line; D049109:Cell Proliferation; D010450:Endopeptidases / Q000378:metabolism*; D004789:Enzyme Activation; D000090683:Hippo Signaling Pathway; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D008840:Microfilament Proteins; D009687:Nuclear Proteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D055550:Protein Stability; D011989:Receptors, Thyrotropin / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: C423985:AMOT protein, human; D000091082:Angiomotins; D018797:Cell Cycle Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D008840:Microfilament Proteins; D009687:Nuclear Proteins; D011989:Receptors, Thyrotropin; D012097:Repressor Proteins; D014157:Transcription Factors; C456659:YY1AP1 protein, human; C432966:ITCH protein, human; D044767:Ubiquitin-Protein Ligases; D017346:Protein Serine-Threonine Kinases; D010450:Endopeptidases; C484854:USP17L2 protein, human