A Computational Model of YAP/TAZ Mechanosensing

摘要: In cell proliferation, stem differentiation, chemoresistance, and tissue organization, the ubiquitous role of YAP/TAZ continues to impact our fundamental understanding in numerous physiological disease systems. is an important signaling nexus integrating diverse mechanical biochemical signals, such as ECM stiffness, adhesion ligand density, or cell-cell contacts, thus strongly influences fate. Recent studies show that sensing dependent on RhoA-regulated stress fibers. However, current remains limited due unknown interaction between canonical Hippo pathway tension. Furthermore, multiscale relationship connecting activity through cytoskeleton dynamics poorly understood. To identify roles key molecules signal transduction, we present a, knowledge, novel computational model pathway. This converts extracellular-matrix properties signals via adhesion, integrates intracellular cascades associated with dynamics. We perform perturbations molecular levels sensitivity analyses predict how various affect activity. Adhesion molecules, FAK, are predicted rescue soft environments RhoA also found changes molecule concentrations result different patterns stiffness response. investigate compare SRF/MAL, which another regulator differentiation. addition, shows unresolved synergistic effect mechanosensing pathways can be explained by LIM-kinase LATS. Overall, provides platform for studying context pathways. used gain, new insights into regulators development, engineering, tumor progression.