Rules of Life at the Interface of Calcium Signaling and Mechanobiology

Living systems process a broad range of internal and external stimuli, respond to environmental constraints, and adapt to various conditions. The functional interactions between components and mechanisms operating at each scale - from molecules to organisms - define the collective “Rules of Life” (RoLs) that govern the emergent properties of biological systems. This review highlights calcium ions (Ca2+), key signaling mediators, which serve as core integrators by facilitating the organization and emergence of structure and function through information encoded in its dynamics. Despite its diverse roles, calcium signaling follows consistent and conserved principles that establish regulatory RoLs that operate across various biological contexts. Here, we examine the key components and functional interactions at the interface of calcium signaling and cellular responses, focusing on calcium-cytoskeleton coupling—how calcium signaling regulates and is regulated by cytoskeletal dynamics. Throughout, we emphasize the importance of computational modeling for the integration of large scale biological data and propose defined RoLs as a modular framework to efficiently capture emergent, multiscalar dynamics of cellular and tissue mechanics across diverse systems. We introduce three RoLs: i) Ca2+ directs cytoskeletal reorganization following stress and damage, ii) Ca2+ modulates actin dynamics to control synapse-like processes across neuronal, immune, and fertilization contexts, and iii) Ca2+ exhibits diverse spatial patterns that both influence and reflect cellular function, contributing to role-specific behaviors. Finally, we address current limitations in integrating cell responses and calcium signaling and outline future directions to develop predictive computational models that unify chemical signaling with cellular organization, including translational applications.