Hippo signaling regulates the nuclear behavior and DNA binding times of YAP and TEAD to control transcription

Kroeger, B; Manning, SA; Mohan, V; Lou, J; Sun, G; Lamont, S; McCann, AJ; Francois, M; Polo, JM; Hinde, E; Harvey, KF

Author(s): Kroeger, B; Manning, SA; Mohan, V; Lou, J; Sun, G; Lamont, S; McCann, AJ; Francois, M; Polo, JM; Hinde, E; Harvey, KF;
Details: Publication Year 2025-07-25,Volume 11,Issue #30,Page eadw4974
Journal Title: Science Advances
Publication Type: Research article
Abstract: Over the past two decades, genetic and proteomic screens have identified the Hippo pathway as a complex signaling network that controls tissue growth and human cancer. Despite these advances, our understanding of how Hippo signaling regulates transcription is less clear. To address this, we used live microscopy to study the nuclear behavior of the major Hippo pathway transcription effectors, YAP and TEADs. We reveal that TEADs are a major determinant of YAP DNA binding and nuclear mobility, while YAP minorly influences TEADs. YAP and TEAD1 associate with DNA for longer periods in cells with intrinsically low Hippo pathway activity and upon acute Hippo pathway perturbation. TEAD1 binds the genome on a broad range of timescales, and this is extended substantially in nuclear condensates. Last, a cancer-associated YAP fusion protein exhibits substantially different biophysical behavior than either YAP or TEAD1. Thus, we reveal that Hippo signaling regulates transcription, in part, by influencing the DNA binding times of YAP and TEADs.
Publisher: American Association for the Advancement of Science
Keywords: Humans; *Transcription Factors/metabolism/genetics; Hippo Signaling Pathway; *DNA-Binding Proteins/metabolism/genetics; *Signal Transduction; TEA Domain Transcription Factors; *Protein Serine-Threonine Kinases/metabolism/genetics; *Cell Nucleus/metabolism; *DNA/metabolism; *Transcription, Genetic; YAP-Signaling Proteins; *Adaptor Proteins, Signal Transducing/metabolism/genetics; Protein Binding; *Nuclear Proteins/metabolism/genetics; *Phosphoproteins/metabolism/genetics
Department(s): Laboratory Research
Publisher's Version: https://doi.org/10.1126/sciadv.adw4974
Open Access at Publisher's Site: https://doi.org/10.1126/sciadv.adw4974
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-08-22 08:45:17

Last Modified: 2025-08-22 08:47:41