title: Negative regulation of the Hippo pathway by E3 ubiquitin ligase ITCH is sufficient to promote tumorigenicity.
abstract: The Hippo tumor suppressor pathway, originally defined in fruit flies, regulates cellular proliferation and survival and exerts profound effects on normal mammalian cell fate and tumorigenesis. The present understanding of Hippo pathway components and mechanisms remains incomplete in cancer. WW domain-containing proteins regulate diverse biological processes through interaction with proline-tyrosine (PPxY)-containing targets. In this study, we report that the E3 ubiquitin ligase ITCH regulates stability of LATS1, a serine/threonine kinase in the Hippo pathway, through protein-protein interaction of the PPxY motifs of LATS1 with the WW domains of ITCH. Ubiquitination of LATS1 catalyzed by ITCH stimulated the proteasomal degradation of LATS1. Furthermore, ITCH-mediated degradation of LATS1 was associated with enhanced cell growth, induction of epithelial-mesenchymal transition, and increased tumorigenicity. Conversely, ITCH depletion increased LATS1 levels, enhancing FAS-induced apoptosis and reducing proliferation, survival, and migration. These phenotypes were rescued when both ITCH and LATS1 were depleted. Together, our results reveal a novel functional link between ITCH and the Hippo pathway, deepening their critical roles in tumorigenesis.
authors.affiliation: The Lautenberg Center for Immunology and Cancer Research, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Zaidoun
authors.initials: Z
authors.lastname: Salah
authors.forename: Gerry
authors.initials: G
authors.lastname: Melino
authors.forename: Rami I
authors.initials: RI
authors.lastname: Aqeilan
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology; D005455:Fluorescent Antibody Technique; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D051379:Mice; D016513:Mice, SCID; D009687:Nuclear Proteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism; D014183:Transplantation, Heterologous; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; C456659:YY1AP1 protein, human; C432966:ITCH protein, human; D044767:Ubiquitin-Protein Ligases; C092745:LATS1 protein, human; D017346:Protein Serine-Threonine Kinases