Department of Biomedical Engineering, Texas A&M University, College Station, TX 77843-3120, USA.
J Theor Biol. 2010 May 21;264(2):593-603. doi: 10.1016/j.jtbi.2010.02.020. Epub 2010 Feb 18.
The role of the actin cytoskeleton in regulating mechanotransduction in response to external forces is complex and incompletely understood. Here, we develop a mathematical model coupling the dynamic disassembly and reassembly of actin stress fibers and associated focal adhesions to the activation of c-jun N-terminal kinase (JNK) in cells attached to deformable matrices. The model is based on the assumptions that stress fibers are pre-extended to a preferred level under static conditions and that perturbations from this preferred level destabilize the stress fibers. The subsequent reassembly of fibers upregulates the rate of JNK activation as a result of the formation of new integrin bonds within the associated focal adhesions. Numerical solutions of the model equations predict that different patterns of matrix stretch result in distinct temporal patterns in JNK activation that compare well with published experimental results. In the case of cyclic uniaxial stretching, stretch-induced JNK activation slowly subsides as stress fibers gradually reorient perpendicular to the stretch direction. In contrast, JNK activation is chronically elevated in response to cyclic equibiaxial stretch. A step change in either uniaxial or equibiaxial stretch results in a short, transient upregulation in JNK that quickly returns to the basal level as overly stretched stress fibers disassemble and are replaced by fibers assembled at the preferred level of stretch. In summary, the model describes a mechanism by which the dynamic properties of the actin cytoskeleton allow cells to adapt to applied forces through turnover and reorganization to modulate intracellular signaling.
肌动蛋白细胞骨架在调节对外力的机械转导中的作用是复杂的，目前还不完全清楚。在这里，我们开发了一个数学模型，该模型将肌动蛋白应力纤维和相关黏着斑的动态解聚和重组与附着在可变形基质上的细胞中 c-jun N 端激酶 (JNK) 的激活耦合在一起。该模型基于以下假设：在静态条件下，应力纤维预先延伸到一个优选的水平，而偏离这个优选水平会使应力纤维不稳定。随后纤维的重新组装会导致新的整合素键在相关黏着斑中形成，从而上调 JNK 的激活速率。模型方程的数值解预测，不同的基质拉伸模式会导致 JNK 激活的不同时间模式，这与已发表的实验结果非常吻合。在周期性单轴拉伸的情况下，随着应力纤维逐渐定向垂直于拉伸方向，拉伸诱导的 JNK 激活缓慢消退。相比之下，周期性等张拉伸会导致 JNK 持续激活。无论是单轴还是等张拉伸的阶跃变化都会导致短暂的 JNK 上调，随着过度拉伸的应力纤维解聚并被组装在优选拉伸水平的纤维取代，JNK 很快恢复到基础水平。总之，该模型描述了一种机制，即肌动蛋白细胞骨架的动态特性允许细胞通过周转和重组来适应施加的力，从而调节细胞内信号转导。
