Valeyev Najl V, Downing A Kristina, Skorinkin Andrei I, Campbell Iain D, Kotov Nikolai V
Department of Biochemistry, University of Oxford, South Parks Road, Oxford, UK.
In Silico Biol. 2006;6(6):545-72.
Cell migration has long been studied by a variety of techniques and many proteins have been implicated in its regulation. Integrins, key proteins that link the cell to the extracellular matrix, are central to adhesion complexes whose turnover defines the rate of cell locomotion. The formation and disassembly of these adhesions is regulated by both intracellular and extracellular factors. In this study we have focused on the Ca2+-dependent protein network (module) that disassembles the adhesion complexes. We have developed a mathematical model that includes the Ca2+-dependent enzymes micro-calpain and phospholipase C (PLC) as well as IP3 receptors and stretch activated Ca2+ channels, all of which have been reported to regulate migration. The model also considers the spatial effects of Ca2+ propagation into lamella. Our model predicts differential activation of calpain at the leading and trailing edges of the cell. Since disassembly of integrin adhesive contacts is proportional to the degree of calpain activation, this leads to cell migration in a preferred direction. We show how the dynamics of Ca2+ spiking affects calpain activation and thus changes the disassembly rate of adhesions. The spiking is controlled by PLC activity and currents through stretch-activated Ca2+ channels. Our model thus combines the effects of various molecular factors and leads to a consistent explanation of the regulation of the rate and direction of cell migration.
长期以来，细胞迁移一直通过各种技术进行研究，许多蛋白质都参与了其调节过程。整合素是将细胞与细胞外基质连接起来的关键蛋白质，对于黏附复合体至关重要，而黏附复合体的更新决定了细胞运动的速率。这些黏附结构的形成和拆解受细胞内和细胞外因素的共同调节。在本研究中，我们聚焦于负责拆解黏附复合体的钙离子依赖性蛋白质网络（模块）。我们构建了一个数学模型，该模型纳入了钙离子依赖性酶微钙蛋白酶和磷脂酶C（PLC）以及肌醇三磷酸受体和牵张激活钙离子通道，所有这些都被报道与细胞迁移调节有关。该模型还考虑了钙离子扩散到片状伪足中的空间效应。我们的模型预测了细胞前缘和后缘钙蛋白酶的差异激活。由于整合素黏附接触的拆解与钙蛋白酶激活程度成正比，这导致细胞向优先方向迁移。我们展示了钙离子尖峰的动态变化如何影响钙蛋白酶激活，进而改变黏附结构的拆解速率。钙离子尖峰受PLC活性和通过牵张激活钙离子通道的电流控制。因此，我们的模型综合了各种分子因素的影响，对细胞迁移速率和方向的调节给出了一致的解释。
