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

Yes-associated protein (YAP) and its homologue TAZ are transducers of several biochemical and biomechanical signals, integrating multiplexed inputs from the microenvironment into higher level cellular functions such as proliferation, differentiation and migration. Emerging evidence suggests that Ca²⁺ is a key second messenger that 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 signalling to investigate how temporal dynamics and crosstalk of signalling pathways interacting with Ca²⁺ can alter the YAP/TAZ response, as observed in experiments. By including six signalling 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 that stimuli, Ca²⁺ transients and frequency-dependent relationships between Ca²⁺ and YAP/TAZ are primarily mediated by cPKC, DAG, CaMKII and F-actin. Simulation results illustrate the role of Ca²⁺ dynamics and CaMKII bistable response in switching the direction of changes in Ca²⁺ -induced YAP/TAZ activity. A 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 underlying mechanisms responsible for the controversial Ca²⁺ -YAP/TAZ relationship observed in experiments. KEY POINTS: YAP/TAZ integrates biochemical and biomechanical inputs to regulate cellular functions, and Ca²⁺ acts as a key second messenger linking cellular inputs to YAP/TAZ. Studies have reported contradictory Ca²⁺ -YAP/TAZ relationships for different cell types and stimuli. A network model of Ca²⁺ -mediated YAP/TAZ signalling was developed to investigate the underlying mechanisms of divergent Ca²⁺ -YAP/TAZ relationships. The model predicts context-dependent Ca²⁺ transient, CaMKII bistable response and frequency-dependent activation of LATS1/2 upstream regulators as mechanisms governing the Ca²⁺ -YAP/TAZ relationship. This study provides new insights into the underlying mechanisms of the controversial Ca²⁺ -YAP/TAZ relationship to better understand the dynamics of cellular functions controlled by YAP/TAZ activity.