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

Abstract

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.

Computational modeling establishes mechanotransduction as a potent modulator of the mammalian circadian clock

“…Moreover, changes in cell shape are known to influence YAP/TAZ nuclear translocation (Scott et al 2021; Eroumée et al 2021). Finally, many other pathways such as calcium signaling cascades are known to play important roles in determining the YAP/TAZ N/C (Khalilimeybodi et al 2023). These various factors provide natural areas for future extensions of our model.…”

Strontium and Copper Co-Doped Multifunctional Calcium Phosphates: Biomimetic and Antibacterial Materials for Bone Implants

“…Ca 2+ activates various intracellular signaling pathways such as yes-associated protein (YAP), wingless integration site (WNT) and mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK)1/2. Through these pathways, Ca 2+ stimulates the expression of osteogenic genes, osteoblast proliferation and MSCs differentiation [35,36]. The addition of elements such as Ca, Zn, Sr and Cu to bone implants is intended to improve their osteogenic properties.…”

“…Ca 2+ activates various intracellular signaling pathways such as yes-associated protein (YAP), wingless integration site (WNT) and mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK)1/2. Through these pathways, Ca 2+ stimulates the expression of osteogenic genes, osteoblast proliferation and MSCs differentiation[35,36].So, the effect of ions released into the culture medium on cell viability was also determined. MSCs and U-2 OS cells were seeded in 96-well plates (1 × 10 4 cells/100 µL/well).…”