TY - JOUR
T1 - Integrative modeling and analysis of signaling crosstalk reveal molecular switches coordinating Yes-associated protein transcriptional activities
AU - Ghomlaghi, Milad
AU - Theocharous, Mandy
AU - Hoang, Nhan
AU - Shin, Sung Young
AU - von Kriegsheim, Alex
AU - O’ Neill, Eric
AU - Zhang, Tao
AU - Nguyen, Lan K.
N1 - Funding Information:
This work was partly funded by a Grant-in-Aid grant (ref. 1123892CC ) from Cancer Council Victoria and an ARC Discovery Project ( DP210103074 ) from the Australia Research Council awarded to L.K.N. L.K.N is also supported by a Mid-Career Research Fellowship from the Victorian Cancer Agency ( MCRF18026 ). The authors acknowledge Professor Roger Daly (Monash University) for assistance with the specific cell lines, and Associate Professor Joseph Rosenbluh (Monash University) for providing oligos for qRT-PCR used in this study. The authors also acknowledge the high-performance computing facilities (MASSIVE) and the computing resources provided by Monash University for the mathematical modeling in this work. The contents of the published material are solely the responsibility of the individual authors and do not reflect the views of the funding agencies.
Funding Information:
This work was partly funded by a Grant-in-Aid grant (ref. 1123892CC) from Cancer Council Victoria and an ARC Discovery Project (DP210103074) from the Australia Research Council awarded to L.K.N. L.K.N is also supported by a Mid-Career Research Fellowship from the Victorian Cancer Agency (MCRF18026). The authors acknowledge Professor Roger Daly (Monash University) for assistance with the specific cell lines, and Associate Professor Joseph Rosenbluh (Monash University) for providing oligos for qRT-PCR used in this study. The authors also acknowledge the high-performance computing facilities (MASSIVE) and the computing resources provided by Monash University for the mathematical modeling in this work. The contents of the published material are solely the responsibility of the individual authors and do not reflect the views of the funding agencies. Conceptualization: L.K.N; methodology and experimental design: L.K.N. and M.G.; mathematical modelling: L.K.N. and M.G.; formal analyses: M.G. M.T. N.H. T.Z. S-Y.S. and L.K.N.; investigation: M.G. M.T. S-Y.S. E.O. A.v.K. and L.K.N.; supervision: L.K.N.; writing original and revised article: L.K.N. and M.G.; project coordination and funding acquisition: L.K.N. The authors declare no competing interests.
Publisher Copyright:
© 2024 The Author(s)
PY - 2024/3/15
Y1 - 2024/3/15
N2 - 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.
AB - 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.
KW - Biological sciences
KW - Cell biology
UR - http://www.scopus.com/inward/record.url?scp=85187306734&partnerID=8YFLogxK
U2 - 10.1016/j.isci.2024.109031
DO - 10.1016/j.isci.2024.109031
M3 - Article
C2 - 38380257
AN - SCOPUS:85187306734
SN - 2589-0042
VL - 27
JO - iScience
JF - iScience
IS - 3
M1 - 109031
ER -
