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

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. [Display omitted] •A new mathematical model of TGF-β/Hippo signaling crosstalk, focusing on YAP complexes•Integrative modeling reveals switch-like behavior of the YAP-SMAD and YAP-p73 complexes•RASSF1A and ITCH are key switch regulators; increasing ITCH sustains YAP-SMAD activity•Protein levels affect switch features, highlighting cellular context in YAP regulation Biological sciences; Cell biology