Extracellular pH and Regulation of Integrin-Ligand Interactions

Abstract

In the tumor and wound microenvironments, the extracellular matrix often exhibits acidic extracellular pH. It is well known that acidic pH can strongly affect processes such as cell adhesion and migration. However, the molecular mechanisms governing these effects have not been established. Here, we consider the hypothesis that acidic extracellular pH directly alters the interactions between cell surface integrin receptors and ECM ligands, which are critical to cell adhesion and migration. We employed Multi-Conformation Continuum Electrostatics to predict amino acid pKa values in the integrin avb3 headpiece, and conducted molecular dynamics simulations at acidic and physiological pH to examine the effect of pH on integrin conformational states. Our results suggest that acidic pH promotes opening of the avb3 headpiece, an important step in activation that can enable more effective ligand-receptor association interactions. This has important implications for downstream cell processes in the cancer and wound environments. We also conducted molecular-level experimental approaches, including flow cytometry and atomic force microscope-enabled force spectroscopy, to further examine the role of pH in regulating integrin-ligand interactions. These molecular-level results are connected to cell-level measurements of adhesion and migration at different pH levels, providing a detailed, multi-scale understanding of how acidic extracellular pH affects cell behavior.