Mechanisms underlying divergent relationships between Ca2+ and YAP/TAZ signaling

Yes-associated protein (YAP) and its homolog TAZ are transducers of several biochemical and biomechanical signals, serving to integrate multiplexed inputs from the microenvironment into higher-level cellular functions such as proliferation, differentiation, apoptosis, migration, and hemostasis. Emerging evidence suggests that Ca2+ is a key second messenger that closely connects microenvironmental input signals and YAP/TAZ regulation. However, studies that directly modulate Ca2+ have reported contradictory YAP/TAZ responses: In some studies, a reduction in Ca2+ influx increases the activity of YAP/TAZ, while in others, an increase in Ca2+ influx activates YAP/TAZ. Importantly, Ca2+ and YAP/TAZ exhibit distinct spatiotemporal dynamics, making it difficult to unravel their connections from a purely experimental approach. In this study, we developed a network model of Ca2+-mediated YAP/TAZ signaling to investigate how temporal dynamics and crosstalk of signaling pathways interacting with Ca2+ can alter YAP/TAZ response, as observed in experiments. By including six signaling modules (e.g., GPCR, IP3-Ca2+, Kinases, RhoA, F-actin, and Hippo-YAP/TAZ) that interact with Ca2+, we investigated both transient and steady-state cell response to Angiotensin II and thapsigargin stimuli. The model predicts stimuli, Ca2+ transient, and frequency-dependent relationships between Ca2+ and YAP/TAZ primarily mediated by signaling species like cPKC, DAG, CaMKII, and F-actin. Model results illustrate the role of Ca2+ dynamics and CaMKII bistable response in switching the direction of changes in Ca2+-induced YAP/TAZ activity for different stimuli. Frequency-dependent YAP/TAZ response revealed the competition between upstream regulators of LATS1/2, leading to the YAP/TAZ non-monotonic response to periodic GPCR stimulation. This study provides new insights into the underlying mechanisms responsible for the controversial Ca2+-YAP/TAZ relationship observed in experiments. ### Competing Interest Statement The authors have declared no competing interest. * Abbreviation : Meaning AKT : protein kinase B Ang II : Angiotensin II Arp2/3 : Actin-related protein 2/3 complex CaMKII : Calcium/calmodulin-dependent protein kinase II DAG : Diacylglycerol ECM : Extracellular matrix ER : Endoplasmic reticulum FAK : focal adhesion kinase GPCRs : G-protein coupled receptors IP3 : Inositol 1,4,5-trisphosphate IP3R : IP3 receptor JNK : c-Jun N-terminal kinase LATS1/2 : Large tumor suppressors 1 and 2 LIMK : LIM kinase mDia : mammalian diaphanous-related formin Merlin : Moesin-ezrin-radixin like MST1/2 : Mammalian STE20-like protein kinase 1/2 Myo : myosin light chain NPCs : nuclear pore complexes PA : Phosphatidic acid PIP2 : Phosphatidylinositol 4,5-bisphosphate PKC : protein kinase C PLCβ : Phospholipase C β PLD : Phospholipase D PMCA : Plasma membrane Ca2+ ATPase PP2A : Protein Phosphatase 2A Pyk2 : protein tyrosine kinase 2 RhoA : Rho family of GTPases ROCK : Rho-associated kinase RyRs : Ryanodine receptors SERCA : Sarco/endoplasmic reticulum Ca2+-ATPase SOCE : Store-operated calcium entry TAZ : Transcriptional coactivator with PDZ-binding motif TEADs : TEA domain transcription factors Tg : Thapsigargin TPC2 : Two-pore channel 2 TRPV4 : Transient receptor potential vanilloid-type 4 YAP : Yes-associated protein