Regulation of Integrin Activation in Acidic Extracellular Microenvironments

Abstract

It is well known that extracellular pH (pHe) becomes acidic in the tumor and wound microenvironments, and that acidic extracellular pH can have profound effects on cell adhesion and migraation processes integral to metastasis and wound healing. However, the molecular mechanisms underlying cellular responses to acidic pHe are largely unknown. Integrin receptors form a physical linkage between cells and the extracellular matrix, and are thus capable of modulating cell adhesion and migration in response to extracellular conditions. Here, we examine the role of acidic pHe in regulating activation of integrin αvβ3, as well as downstream consequences for cell-level processes. Employing atomistic molecular dynamics simulations, we find that acidic pHe promotes opening of the αvβ3 headpiece, indicating that acidic pH can promote integrin activation via an outside-in mechanism. In agreement with these simulations, flow cytometry and atomic force microscope-mediated force spectroscopy assays of integrin αvβ3 on live cells demonstrate increased levels of integrin activation when cells are exposed to acidic pHe. Finally, cell morphology and migration measurements demonstrate that cells respond to acidic pHe in a manner that is consistent with increased integrin activation. These multiscale computational and experimental results suggest a new mechanism of integrin activation regulation in regions of acidic extracellular pH, with associated implications for cell adhesion and migration in wound healing and cancer.