Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
PLoS One. 2011 Jan 19;6(1):e15746. doi: 10.1371/journal.pone.0015746.
Acidic extracellular pH is characteristic of the cell microenvironment in several important physiological and pathological contexts. Although it is well established that acidic extracellular pH can have profound effects on processes such as cell adhesion and migration, the underlying molecular mechanisms are largely unknown. Integrin receptors physically connect cells to the extracellular matrix, and are thus likely to modulate cell responses to extracellular conditions. Here, we examine the role of acidic extracellular pH in regulating activation of integrin α(v)β(3). Through computational molecular dynamics simulations, we find that acidic extracellular pH promotes opening of the α(v)β(3) headpiece, indicating that acidic pH can thereby facilitate integrin activation. This prediction is consistent with our flow cytometry and atomic force microscope-mediated force spectroscopy assays of integrin α(v)β(3) on live cells, which both demonstrate that acidic pH promotes activation at the intact cell surface. Finally, quantification of cell morphology and migration measurements shows that acidic extracellular pH affects cell behavior in a manner that is consistent with increased integrin activation. Taken together, these computational and experimental results suggest a new and complementary mechanism of integrin activation regulation, with associated implications for cell adhesion and migration in regions of altered pH that are relevant to wound healing and cancer.
酸性细胞外 pH 值是几种重要生理和病理情况下细胞微环境的特征。尽管酸性细胞外 pH 值可对细胞黏附和迁移等过程产生深远影响已得到广泛证实，但其中的潜在分子机制在很大程度上仍不清楚。整合素受体将细胞与细胞外基质物理连接，因此很可能调节细胞对细胞外环境的反应。在这里，我们研究了酸性细胞外 pH 值在调节整合素 α(v)β(3)激活中的作用。通过计算分子动力学模拟，我们发现酸性细胞外 pH 值促进了 α(v)β(3)的头部打开，表明酸性 pH 值可以促进整合素的激活。这一预测与我们在活细胞上进行的整合素 α(v)β(3)流式细胞术和原子力显微镜介导的力谱检测结果一致，两者均表明酸性 pH 值促进了完整细胞表面的激活。最后，细胞形态的量化和迁移测量表明，酸性细胞外 pH 值以一种与整合素激活增加一致的方式影响细胞行为。综上所述，这些计算和实验结果表明了一种新的整合素激活调节的补充机制，与伤口愈合和癌症等 pH 值改变相关区域的细胞黏附和迁移有关。
