acidic extracellular ph promotes activation of integrin αvβ3酸性ph值细胞外促进了整合素的活化αvβ3.pdfVIP

Acidic Extracellular pH Promotes Activation of Integrin avb3 1 1 1,2 Ranjani K. Paradise , Douglas A. Lauffenburger , Krystyn J. Van Vliet * 1 Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America, 2 Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America 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 a b . Through computational molecular dynamics v 3 simulations, we find that acidic extracellular pH promotes opening of the av b3 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 av b3 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 consisten