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EXTRACELLULAR MATRIX, CELL INTERACTIONS

Increased extracellular pressure enhances cancer cell integrin-binding affinity through phosphorylation of β₁-integrin at threonine 788/789

Departments of ¹Surgery, ²Anesthesiology, and ³Anatomy and Cell Biology, John D. Dingell VA Medical Center and Wayne State University, Detroit, Michigan; ⁴Department of Immunology and Microbiology, University of Michigan, Ann Arbor, Michigan; ⁵Oncology Research Institute, Greenville Hospital System, Greenville, South Carolina; and ⁶Department of Biological Sciences, Clemson University, Clemson, South Carolina

Submitted 8 July 2008 ; accepted in final form 11 November 2008

Increased extracellular pressure stimulates β₁-integrin-dependent cancer cell adhesion. We asked whether pressure-induced adhesion is mediated by changes in β₁-integrin binding affinity or avidity and whether these changes are phosphorylation dependent. We evaluated integrin affinity and clustering in human SW620 colon cancer cells by measuring differences in binding between soluble Arg-Gly-Asp (RGD)-Fc ligands and RGD-Fc-F(ab')₂ multimeric complexes under ambient and 15-mmHg increased pressures. Phosphorylation of β₁-integrin S785 and T788/9 residues in SW620 and primary malignant colonocytes was assessed in parallel. We further used GD25-β₁-integrin-null murine fibroblasts stably transfected with either wild-type β_1A-integrin, S785A, TT788/9AA, or T788D mutants to investigate the role of β₁-integrin site-specific phosphorylation. SW620 binding of RGD-Fc-F(ab')₂ multimeric complexes, but not soluble RGD-Fc ligands, was sensitive to integrin clustering. RGD-Fc ligand binding was significantly increased under elevated pressure, suggesting that pressure modulates β₁-integrin affinity. Pressure stimulated both β₁-integrin S785 and T788/9 phosphorylation. GD25-β_1A-integrin wild-type and S785A cells displayed an increase in adhesion to fibronectin under elevated pressure, an effect absent in β₁-integrin-null and TT788/9AA cells. T788D substitution significantly elevated basal cell adhesion but displayed no further increase under pressure. These results suggest pressure-induced cell adhesion is mediated by β₁-integrin T788/9 phosphorylation-dependent changes in integrin binding affinity.

adhesion; mechanotransduction; metastasis