Premium
Elucidation of WW domain ligand binding specificities in the Hippo pathway reveals STXBP 4 as YAP inhibitor
Author(s) -
Vargas Rebecca E,
Duong Vy Thuy,
Han Han,
Ta Albert Paul,
Chen Yuxuan,
Zhao Shiji,
Yang Bing,
Seo Gayoung,
Chuc Kimberly,
Oh Sunwoo,
El Ali Amal,
Razorenova Olga V,
Chen Junjie,
Luo Ray,
Li Xu,
Wang Wenqi
Publication year - 2019
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2019102406
Subject(s) - ww domain , hippo signaling pathway , microbiology and biotechnology , biology , cytoskeleton , actin cytoskeleton , proteome , plasma protein binding , human proteome project , signal transduction , cell , biochemistry , proteomics , gene
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, STXBP 4, as a negative regulator of YAP . Mechanistically, STXBP 4 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, STXBP 4 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 STXBP 4 as a player in actin cytoskeleton tension‐mediated Hippo pathway regulation.