Elucidation of WW domain ligand binding specificities in the Hippo pathway reveals STXBP4 as YAP inhibitor

Rebecca E. Vargas, Vy Thuy Duong, Han Han, Albert Paul Ta, Yuxuan Chen, Shiji Zhao, Bing Yang, Gayoung Seo, Kimberly Chuc, Sunwoo Oh, Amal El Ali, Olga V. Razorenova, Junjie Chen, Ray Luo, Xu Li, Wenqi Wang

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

The 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 α-catenin and a group of Hippo PY motif-containing components/regulators to inhibit YAP, a process that is regulated by actin cytoskeleton tension. Interestingly, STXBP4 is a potential tumor suppressor for human kidney cancer, whose downregulation is correlated with YAP activation in clear cell renal cell carcinoma. Taken together, our study not only elucidates the WW domain binding specificity for the Hippo pathway, but also reveals STXBP4 as a player in actin cytoskeleton tension-mediated Hippo pathway regulation.

Original languageEnglish (US)
Article numbere102406
JournalEMBO Journal
Volume39
Issue number1
DOIs
StatePublished - Jan 2 2020

Keywords

  • PY motif
  • STXBP4
  • WW domain
  • YAP
  • the Hippo pathway

ASJC Scopus subject areas

  • General Neuroscience
  • Molecular Biology
  • General Biochemistry, Genetics and Molecular Biology
  • General Immunology and Microbiology

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