Unraveling context-specific mechanisms governing calcium-YAP/TAZ distinct relationships through computational modeling

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 calcium 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 calcium can alter YAP/TAZ response. By including six signaling modules (e.g., GPCR, IP3- Ca2+, Kinases, RhoA, F-actin, and Hippo-YAP/TAZ) that interact with calcium, we investigated both transient and steady-state cell response to Angiotensin II, Thapsigargin, and ECM stiffness stimuli. The model predicts a context-dependent relationship between calcium signaling and YAP/TAZ activation primarily mediated by PKC, DAG, CaMKII, and F-actin. Model results illustrate the role of calcium dynamics and CaMKII bistable response in switching the direction of changes in Ca2+-induced YAP/TAZ activity. 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. We also identified key roles of Ca2+ and CaMKII dynamics in shaping the nonlinear relationship between cell size and YAP/TAZ activity. The model predicts Ca2+-YAP/TAZ distinct relationships in different settings consistent with experiments. The model predictions provide new insights into the underlying mechanisms responsible for the controversial Ca2+-YAP/TAZ relationship observed in experiments.