title: Acidic extracellular pH promotes activation of integrin α(v)β(3).
abstract: 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.
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
authors.forename: Ranjani K
authors.initials: RK
authors.lastname: Paradise
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Lauffenburger
authors.forename: Krystyn J
authors.initials: KJ
authors.lastname: Van Vliet
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D002465:Cell Movement; D002478:Cells, Cultured; D003198:Computer Simulation; D005109:Extracellular Matrix / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D018625:Microscopy, Atomic Force; D056004:Molecular Dynamics Simulation
chemical_list: D039302:Integrin alphaVbeta3