title: Tankyrase Inhibitors Target YAP by Stabilizing Angiomotin Family Proteins.
abstract: As the key effector in the Hippo pathway, YAP was identified as an oncoprotein whose expression is elevated in various human cancers. However, the development of potentially therapeutic compounds targeting YAP has been slow and limited. Here, we find that tankyrase inhibitors suppress YAP activity. This effect is mediated by anigomotin (AMOT) family proteins. Tankyrases associate with AMOT family proteins and promote their degradation through E3 ligase RNF146. By antagonizing tankyrase activity, tankyrase inhibitors stabilize AMOT family proteins, thereby suppressing YAP oncogenic functions. Together, our studies not only demonstrate the tankyrase-RNF146-AMOT axis as an upstream pathway regulating YAP but also reveal a therapeutic opportunity in targeting YAP for cancer treatment.
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. Electronic address: wwang5@mdanderson.org.
authors.forename: Wenqi
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Nan
authors.initials: N
authors.lastname: Li
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Xu
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: My Kim
authors.initials: MK
authors.lastname: Tran
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Han
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. Electronic address: jchen8@mdanderson.org.
authors.forename: Junjie
authors.initials: J
authors.lastname: Chen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000091082:Angiomotins; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D057809:HEK293 Cells; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D061986:MCF-7 Cells; D008565:Membrane Proteins / Q000378:metabolism*; D008840:Microfilament Proteins; D010750:Phosphoproteins / Q000378:metabolism*; D011485:Protein Binding; D055550:Protein Stability; D059748:Proteolysis; D013450:Sulfones / Q000494:pharmacology; D038501:Tankyrases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014157:Transcription Factors; D014230:Triazoles / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D000091102:YAP-Signaling Proteins
chemical_list: C423985:AMOT protein, human; D048868:Adaptor Proteins, Signal Transducing; D000091082:Angiomotins; D004791:Enzyme Inhibitors; C582305:G007-LK; D006575:Heterocyclic Compounds, 3-Ring; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D008840:Microfilament Proteins; D010750:Phosphoproteins; D013450:Sulfones; D014157:Transcription Factors; D014230:Triazoles; C544261:XAV939; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C561932:RNF146 protein, human; D044767:Ubiquitin-Protein Ligases; D038501:Tankyrases