title: Angiomotin stabilization by tankyrase inhibitors antagonizes constitutive TEAD-dependent transcription and proliferation of human tumor cells with Hippo pathway core component mutations.
abstract: The evolutionarily conserved Hippo inhibitory pathway plays critical roles in tissue homeostasis and organ size control, while mutations affecting certain core components contribute to tumorigenesis. Here we demonstrate that proliferation of Hippo pathway mutant human tumor cells exhibiting high constitutive TEAD transcriptional activity was markedly inhibited by dominant negative TEAD4, which did not inhibit the growth of Hippo wild-type cells with low levels of regulatable TEAD-mediated transcription. The tankyrase inhibitor, XAV939, identified in a screen for inhibitors of TEAD transcriptional activity, phenocopied these effects independently of its other known functions by stabilizing angiomotin and sequestering YAP in the cytosol. We also identified one intrinsically XAV939 resistant Hippo mutant tumor line exhibiting lower and less durable angiomotin stabilization. Thus, angiomotin stabilization provides a new mechanism for targeting tumors with mutations in Hippo pathway core components as well as a biomarker for sensitivity to such therapy.
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Albino
authors.initials: A
authors.lastname: Troilo
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Erica K
authors.initials: EK
authors.lastname: Benson
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Davide
authors.initials: D
authors.lastname: Esposito
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Rachel-Ann A
authors.initials: RA
authors.lastname: Garibsingh
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: E Premkumar
authors.initials: EP
authors.lastname: Reddy
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Sathish Kumar
authors.initials: SK
authors.lastname: Mungamuri
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Aaronson
mesh_terms: D000091082:Angiomotins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology*; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology*; D000090683:Hippo Signaling Pathway; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D008840:Microfilament Proteins; D009124:Muscle Proteins / Q000378:metabolism*; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D000091262:TEA Domain Transcription Factors; D038501:Tankyrases / Q000037:antagonists & inhibitors; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D000091082:Angiomotins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D008840:Microfilament Proteins; D009124:Muscle Proteins; D017346:Protein Serine-Threonine Kinases; D000091262:TEA Domain Transcription Factors; D038501:Tankyrases; D014157:Transcription Factors; C423985:AMOT protein, human; C486309:TEAD4 protein, human; C544261:XAV939; C418109:TNKS protein, human
keywords: TEAD; YAP; angiomotin; tankyrase inhibitors; tumor cell proliferation