Shuaib Aban, Hartwell Adam, Kiss-Toth Endre, Holcombe Mike
Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom.
Department of Computer Science, University of Sheffield, Sheffield, United Kingdom.
PLoS One. 2016 May 31;11(5):e0156139. doi: 10.1371/journal.pone.0156139. eCollection 2016.
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.
通过丝裂原活化蛋白激酶（MAPK）途径进行的信号转导在进化上高度保守。许多细胞利用这些途径来解读其环境的变化并做出相应反应。这些途径对于触发多种细胞反应（如存活、凋亡、分化和增殖）至关重要。尽管不同MAPK途径之间的相互作用很复杂，但它们对原始信号仍保持高度的保真度和特异性。有许多理论解释在这种复杂情况下保真度和特异性是如何产生的；途径的时空调节和反馈回路被认为非常重要。本文提出了一个基于主体的计算模型，该模型探讨了多区室化以及这如何影响MAPK级联激活的动力学。该模型表明，多区室化与周期性的MAPK激酶（MAPKK）激活可能是系统中出现振荡和超敏感性的关键因素。最后，该模型还建立了级联组件的空间排列与时间激活机制之间的联系，以及两者如何共同促进MAPK介导信号传导的保真度和特异性。
