Integrative modeling and analysis of signaling crosstalk reveal molecular switches coordinating Yes-associated protein transcriptional activities

Milad Ghomlaghi; Mandy Theocharous; Nhan Hoang; Sung-Young Shin; Alex von Kriegsheim; Eric O' Neill; Tao Zhang; Lan K Nguyen

doi:10.1016/j.isci.2024.109031

Integrative modeling and analysis of signaling crosstalk reveal molecular switches coordinating Yes-associated protein transcriptional activities

iScience. 2024 Jan 26;27(3):109031. doi: 10.1016/j.isci.2024.109031. eCollection 2024 Mar 15.

Authors

Milad Ghomlaghi^{1

2}, Mandy Theocharous^{1

2}, Nhan Hoang^{1

2}, Sung-Young Shin^{1

2}, Alex von Kriegsheim³, Eric O' Neill⁴, Tao Zhang^{1

2}, Lan K Nguyen^{1

2}

Affiliations

¹ Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, VIC 3800, Australia.
² Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia.
³ Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, The University of Edinburgh, Crewe Road South, Edinburgh EH4 2XR, UK.
⁴ CRUK/MRC Institute for Radiation Oncology and Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.

Abstract

The transcriptional co-activator YAP forms complexes with distinct transcription factors, controlling cell fate decisions, such as proliferation and apoptosis. However, the mechanisms underlying its context-dependent function are poorly defined. This study explores the interplay between the TGF-β and Hippo pathways and their influence on YAP's association with specific transcription factors. By integrating iterative mathematical modeling with experimental validation, we uncover molecular switches, predominantly controlled by RASSF1A and ITCH, which dictate the formation of YAP-SMAD (proliferative) and YAP-p73 (apoptotic) complexes. Our results show that RASSF1A enhances the formation of apoptotic complexes, whereas ITCH promotes the formation of proliferative complexes. Notably, higher levels of ITCH transform YAP-SMAD activity from a transient to a sustained state, impacting cellular behaviors. Extending these findings to various breast cancer cell lines highlights the role of cellular context in YAP regulation. Our study provides new insights into the mechanisms of YAP transcriptional activities and their therapeutic implications.

Keywords: Biological sciences; Cell biology.