Acidic Extracellular pH Promotes Activation of Integrin [alpha]v[beta]3

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 avb3. Through computational molecular dynamics simulations, we find that acidic extracellular pH promotes opening of the avb3 headpiece, indicating that acidic pH can thereby facilitate integrin activation. This prediction is consistent with our flow cytometry and atomic force microscopemediated force spectroscopy assays of integrin avb3 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. Citation: Paradise RK, Lauffenburger DA, Van Vliet KJ (2011) Acidic Extracellular pH Promotes Activation of Integrin avb3. PLoS ONE 6(1): e15746. doi:10.1371/ journal.pone.0015746 Editor: Jean Kanellopoulos, University Paris Sud, France Received September 17, 2010; Accepted November 26, 2010; Published January 19, 2011 Copyright: 2011 Paradise et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The work was supported by Award Number T32EB006348 from the National Institute of Biomedical Imaging and Bioengineering and the MIT Collamore-Rogers Fellowship (RKP), the NIH Cell Migration Consortium Grant U54-GM069668 (DAL and RKP), the NSF CAREER Award (KJVV and RKP), and the Singapore-MIT Alliance for Research & Technology (SMART) Biosystems & Micromechanics (BioSyM) Interdisciplinary Research Group (KJVV and RKP). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: [email protected]