Premium
Phosphoinositide 3‐kinase (PI3K) activation and actin dynamics within force sensing anchors are required to stabilize VLA‐4 integrin‐mediated leukocyte adhesion
Author(s) -
Rullo Jacob,
Becker Henry,
Hyduk Sharon,
Cybulsky Myron
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.55.3
Subject(s) - actin cytoskeleton , microbiology and biotechnology , integrin , actin , chemistry , actin remodeling , adhesion , cytoskeleton , cell adhesion , cell adhesion molecule , biophysics , biology , receptor , cell , biochemistry , organic chemistry
During inflammation, leukocytes modulate α4β1 (VLA‐4) integrin avidity in order to rapidly form stable nascent adhesive contacts to VCAM‐1‐expressing endothelial cells and resist detachment forces imparted by the flowing blood. Linkage to the actin cytoskeleton is critical for integrin function, yet the exact role of the actin cytoskeleton in leukocyte adhesion stabilization under conditions of fluid forces remains poorly understood. We report that mechanical forces imparted by flow induce formation of upstream tension‐bearing anchors attached to the VCAM‐1‐coated surface and Rac, but not Cdc42, small GTPase‐dependent polymerization of F‐actin within these structures. These structures are critical for adhesion stabilization, since disruption of actin polymerization dramatically inhibits VLA‐4‐dependent resistance to detachment, but does not affect VLA‐4 expression, affinity modulation, clustering or constitutive linkage to F‐actin. A key mediator of force‐induced Rac activation and actin polymerization is PI3K. Live cell imaging revealed accumulation of PIP3 within tension‐bearing anchors and blockade of PI3K or deficiency of PI3Kgamma isoform reproduced the adhesion defect produced by inhibition of actin polymerization. Our results implicate a novel mechanism in the leukocyte adhesion cascade necessary for stabilization of nascent adhesive contacts. Research supported by a CGS CIHR Doctoral Award.