Welf Erik S, Haugh Jason M
Department of Chemical and Biomolecular Engineering, North Carolina State University, Box 7905, Raleigh, NC 27695, USA.
Cell Mol Bioeng. 2010 Mar 1;3(1):30-39. doi: 10.1007/s12195-010-0100-8.
Cell migration is regulated by processes that control adhesion to extracellular matrix (ECM) and force generation. While our fundamental understanding of how these control mechanisms are actuated at the molecular level (signal transduction) has been refined over many years, appreciation of their dynamics has grown more recently. Here, we formulate and analyze by stochastic simulation a quantitative model of signaling mediated by the integrin family of adhesion receptors. Nascent adhesions foster the activation of the small GTPase Rac by at least two distinct signaling pathways, one of which involves tyrosine phosphorylation of the scaffold protein paxillin and formation of multiprotein complexes containing the guanine nucleotide exchange factor DOCK180. Active Rac promotes protrusion of the cell's leading edge, which in turn enhances the rate of nascent adhesion nucleation; we call this feedback mechanism the core protrusion cycle. Protrusion is antagonized by stable adhesions, which form by myosin-dependent maturation of nascent adhesions, and we propose here a feedforward mechanism mediated by the tyrosine kinase c-Src by which this antagonism is regulated so as to allow transient protrusion at higher densities of ECM. We show that this "buffering of inhibition" mechanism, coupled with the core protrusion cycle, is capable of tuning the frequencies of protrusion and adhesion maturation events.
细胞迁移受控制与细胞外基质（ECM）黏附及力产生的过程调节。尽管多年来我们对这些控制机制在分子水平（信号转导）如何启动的基本理解已得到完善，但对其动力学的认识直到最近才有所增加。在此，我们通过随机模拟构建并分析了一个由整合素家族黏附受体介导的信号传导定量模型。新生黏附通过至少两条不同的信号通路促进小GTP酶Rac的激活，其中一条通路涉及支架蛋白桩蛋白的酪氨酸磷酸化以及包含鸟嘌呤核苷酸交换因子DOCK180的多蛋白复合物的形成。活性Rac促进细胞前缘的突出，这反过来又提高了新生黏附成核的速率；我们将这种反馈机制称为核心突出循环。突出受到稳定黏附的拮抗，稳定黏附通过新生黏附的肌球蛋白依赖性成熟形成，并且我们在此提出一种由酪氨酸激酶c-Src介导的前馈机制，通过该机制调节这种拮抗作用，以便在更高密度的ECM下允许短暂突出。我们表明，这种“抑制缓冲”机制与核心突出循环相结合，能够调节突出和黏附成熟事件的频率。
