YAP is a co-transcription factor that is involved in both proliferative and apoptotic gene expression. Depending on the network condition, YAP binds to different transcription factors with opposite functions in cell homeostasis. Its activity is coordinated by different signalling pathways in cell. In cancerous cells, the TGFβ pathway recruits YAP for oncogenic gene transcription by promoting formation of the YAP-SMAD complex. On the other hand, the Hippo pathway activates RASSF1A to enhance apoptotic transcription by upregulating the YAP-p73 complex. Therefore, depending on the network status YAP can accelerate or suppress tumour progression. Despite its crucial role in governing the proliferative-apoptotic balance, the mechanisms by which YAP does so remains poorly understood. Obtaining a mechanistic understanding of the regulatory mechanisms of YAP activities will enable us to tip the balance towards an apoptotic program in tumour cells.
Here we integrated computational mechanistic modelling, in-vitro experiments and -omic data analysis to characterize how YAP activities are coordinated. We constructed a new mathematical model for the TGFβ and Hippo pathways crosstalk validated by the experimental tests. Our analyses unveiled ITCH as a previously unknown regulator of YAP oncogenic and apoptotic activities. At low levels of ITCH, YAP displays a higher affinity for p73 binding that promotes apoptotic transcription. However, high concentrations of ITCH sharply switches YAP binding partners from p73 to SMAD, thereby enhancing proliferative gene expression. Simulations also indicate YAP activation responds to ITCH overexpression in a switch-like fashion. Adjusting the new constructed model to 40 different cancer cell lines using the CCLE database enabled us to investigate the ITCH-mediated YAP switch-like behaviour in different cellular contexts. This analysis revealed a strong correlation between the impact of ITCH in regulating YAP activities and its essentiality in maintaining cell viability. Overall, our integrated analysis provides novel network-level insights into YAP biology and suggests ITCH as a key concurrent regulator of apoptotic and proliferative gene expression and a potential new therapeutic target for cancer.