title: Conformational coupling of integrin and Thy-1 regulates Fyn priming and fibroblast mechanotransduction.
abstract: Progressive fibrosis is characterized by excessive deposition of extracellular matrix (ECM), resulting in gross alterations in tissue mechanics. Changes in tissue mechanics can further augment scar deposition through fibroblast mechanotransduction. In idiopathic pulmonary fibrosis, a fatal form of progressive lung fibrosis, previous work has shown that loss of Thy-1 (CD90) expression in fibroblasts correlates with regions of active fibrogenesis, thus representing a pathologically relevant fibroblast subpopulation. We now show that Thy-1 is a regulator of fibroblast rigidity sensing. Thy-1 physically couples to inactive αvβ3 integrins via its RGD-like motif, altering baseline integrin avidity to ECM ligands and also facilitating preadhesion clustering of integrin and membrane rafts via Thy-1's glycophosphatidylinositol tether. Disruption of Thy-1-αvβ3 coupling altered recruitment of Src family kinases to adhesion complexes and impaired mechanosensitive, force-induced Rho signaling, and rigidity sensing. Loss of Thy-1 was sufficient to induce myofibroblast differentiation in soft ECMs and may represent a physiological mechanism important in wound healing and fibrosis.
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30332.
authors.forename: Vincent F
authors.initials: VF
authors.lastname: Fiore
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30332.
authors.forename: Patrick W
authors.initials: PW
authors.lastname: Strane
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30332.
authors.forename: Anton V
authors.initials: AV
authors.lastname: Bryksin
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109.
authors.forename: Eric S
authors.initials: ES
authors.lastname: White
authors.affiliation: Division of Respiratory Medicine, Department of Pediatrics, University of California, Rady Children's Hospital, San Diego, CA 92105.
authors.forename: James S
authors.initials: JS
authors.lastname: Hagood
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30332 Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA 30332 thomas.barker@bme.gatech.edu.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Barker
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000502:physiology; D005347:Fibroblasts / Q000502:physiology*; D022001:Focal Adhesions / Q000378:metabolism; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D040542:Mechanotransduction, Cellular; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051076:Proto-Oncogene Proteins c-fyn / Q000378:metabolism*; D018800:Thy-1 Antigens / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D020742:rhoA GTP-Binding Protein
chemical_list: D039302:Integrin alphaVbeta3; D018800:Thy-1 Antigens; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein