Bone cells are exposed to dynamic mechanical stimulation that is transduced into cellular responses by mechanotransduction mechanisms. The extracellular matrix (ECM) provides a physical link between loading and bone cells, where mechanoreceptors, such as integrins, initiate mechanosensation. Though this relationship is well studied, the dynamic interplay between mechanosensation, mechanotransduction and cellular responses is unclear. A hybrid-multiscale model combining molecular, cellular and tissue interactions was developed to examine links between integrins’ mechanosensation and effects on mechanotransduction, ECM modulation and cell-ECM interaction. The model shows that altering integrin mechanosensitivity threshold (MT) increases mechanotransduction durations from hours to beyond 4 days, where bone formation starts. This is relevant to bone, where it is known that a brief stimulating period provides persistent influences for over 24 hours. Furthermore, the model forecasts that integrin heterogeneity, with respect to MT, would be able to induce sustained increase in pERK baseline > 15% beyond 4 days. This is analogous to the emergence of molecular mechanical memory signalling dynamics. Therefore, the model can provide a greater understanding of mechanical adaptation to differential mechanical responses at different times. Given reduction of bone sensitivity to mechanical stimulation with age, these findings may lead towards useful therapeutic targets for upregulation of bone mass.
Spatio-temporal regulation of intracellular signalling networks is key to normal cellular physiology; dysregulation of which leads to disease. The family of three mammalian tribbles proteins has emerged as an important controller of signalling via regulating the activity of mitogen activated protein kinases (MAPK), the PI3-kinase induced signalling network and E3 ubiquitin ligases. However, the importance of potential redundancy in the action of tribbles and how the differences in affinities for the various binding partners may influence signalling control is currently unclear. We report that tribbles proteins can bind to an overlapping set of MAPK-kinases (MAPKK) in live cells and dictate the localisation of the complexes. Binding studies in transfected cells reveal common regulatory mechanisms and suggest that tribbles and MAPKs may interact with MAPKKs in a competitive manner. Computational modelling of the impact of tribbles on MAPK activation suggests a high sensitivity of this system to changes in tribbles levels, highlighting that these proteins are ideally placed to control the dynamics and balance of activation of concurrent signalling pathways.
Signal transduction through the Mitogen Activated Protein Kinase (MAPK) pathways is evolutionarily highly conserved. Many cells use these pathways to interpret changes to their environment and respond accordingly. The pathways are central to triggering diverse cellular responses such as survival, apoptosis, differentiation and proliferation. Though the interactions between the different MAPK pathways are complex, nevertheless, they maintain a high level of fidelity and specificity to the original signal. There are numerous theories explaining how fidelity and specificity arise within this complex context; spatio-temporal regulation of the pathways and feedback loops are thought to be very important. This paper presents an agent based computational model addressing multi-compartmentalisation and how this influences the dynamics of MAPK cascade activation. The model suggests that multi-compartmentalisation coupled with periodic MAPK kinase (MAPKK) activation may be critical factors for the emergence of oscillation and ultrasensitivity in the system. Finally, the model also establishes a link between the spatial arrangements of the cascade components and temporal activation mechanisms, and how both contribute to fidelity and specificity of MAPK mediated signalling.
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