biostudies-otherUnknownProf. Wenqi WangHHS | National Institutes of Health (NIH)U.S. Department of Defense (DOD)American Cancer Society (ACS)HHS | NIH | National Cancer Institute (NCI)HHS | NIH | National Institute of General Medical Sciences (NIGMS)The EMBO Journalhttps://www.ebi.ac.uk/biostudies/studies/S-SCDT-EMBOJ-2019-102406The Hippo pathway, which plays a critical role in organ size control and cancer, features numerous WW domain-based protein-protein interactions. However, ~100 WW domains and 2,000 PY motif-containing peptide ligands are found in the human proteome, raising a "WW-PY" binding specificity issue in the Hippo pathway. In this study, we have established the WW domain binding specificity for Hippo pathway components and uncovered a unique amino acid sequence required for it. By using this criterion, we have identified a WW domain-containing protein, STXBP4, as a negative regulator of YAP. Mechanistically, STXBP4 assembles a protein complex comprising ?-catenin and a group of Hippo PY motif-containing components/regulators to inhibit YAP, a process that is regulated by actin cytoskeleton tension. biostudies-otherW81XWH-09-1-0409GM055246P30 CA062203RSG-18-009-01-CCGGM130367GM126048T32 EB009418-08Vy, Thuy DuongProf. Junjie ChenKimberly ChucSunwoo OhAlbert, Paul TaOlga RazorenovaYuxuan ChenProf. Ray LuoProf. Wenqi WangXu LiHan HanShiji ZhaoMs. Bing YangAmal, El AliRebecca VargasGayoung SeofalseElucidation of WW domain ligand binding specificities in the Hippo pathway reveals STXBP4 as YAP inhibitorThe Hippo pathway, which plays a critical role in organ size control and cancer, features numerous WW domain-based protein-protein interactions. However, ~100 WW domains and 2,000 PY motif-containing peptide ligands are found in the human proteome, raising a "WW-PY" binding specificity issue in the Hippo pathway. In this study, we have established the WW domain binding specificity for Hippo pathway components and uncovered a unique amino acid sequence required for it. By using this criterion, we have identified a WW domain-containing protein, STXBP4, as a negative regulator of YAP. Mechanistically, STXBP4 assembles a protein complex comprising ?-catenin and a group of Hippo PY motif-containing components/regulators to inhibit YAP, a process that is regulated by actin cytoskeleton tension. 2020-01-13T21:00:54Z2020-01-13T21:00:54Z2020-01-13T21:00:54ZS-SCDT-EMBOJ-2019-10240610.15252/embj.2019102406