title: The fibronectin synergy site re-enforces cell adhesion and mediates a crosstalk between integrin classes.
abstract: Fibronectin (FN), a major extracellular matrix component, enables integrin-mediated cell adhesionviabinding of α5β1, αIIbβ3 and αv-class integrins to an RGD-motif. An additional linkage for α5 and αIIb is the synergy site located in close proximity to the RGD motif. We report that mice with a dysfunctional FN-synergy motif (Fn1syn/syn) suffer from surprisingly mild platelet adhesion and bleeding defects due to delayed thrombus formation after vessel injury. Additional loss of β3 integrins dramatically aggravates the bleedings and severely compromises smooth muscle cell coverage of the vasculature leading to embryonic lethality. Cell-based studies revealed that the synergy site is dispensable for the initial contact of α5β1 with the RGD, but essential to re-enforce the binding of α5β1/αIIbβ3 to FN. Our findings demonstrate a critical role for the FN synergy site when external forces exceed a certain threshold or when αvβ3 integrin levels decrease below a critical level.
authors.affiliation: Department of Biochemistry and Molecular Biology, Universitat de València, Burjassot, Spain.|Estructura de Recerca Interdisciplinar en Biotecnologia i Biomedicina, Universitat de València, Burjassot, Spain.
authors.forename: Maria
authors.identifier: 0000-0001-9562-5430
authors.initials: M
authors.lastname: Benito-Jardón
authors.affiliation: Walter Brendel Centre of Experimental Medicine, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Klapproth
authors.affiliation: Department of Biochemistry and Molecular Biology, Universitat de València, Burjassot, Spain.|Estructura de Recerca Interdisciplinar en Biotecnologia i Biomedicina, Universitat de València, Burjassot, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Gimeno-LLuch
authors.affiliation: Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Munich, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Petzold
authors.affiliation: Eidgenössische Technische Hochschule Zürich, Basel, Switzerland.
authors.forename: Mitasha
authors.initials: M
authors.lastname: Bharadwaj
authors.affiliation: Eidgenössische Technische Hochschule Zürich, Basel, Switzerland.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Müller
authors.affiliation: Walter Brendel Centre of Experimental Medicine, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Zuchtriegel
authors.affiliation: Walter Brendel Centre of Experimental Medicine, Ludwig-Maximilians-Universität München, Munich, Germany.|Departement of Otorhinolaryngology, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Christoph A
authors.initials: CA
authors.lastname: Reichel
authors.affiliation: Department of Biochemistry and Molecular Biology, Universitat de València, Burjassot, Spain.|Estructura de Recerca Interdisciplinar en Biotecnologia i Biomedicina, Universitat de València, Burjassot, Spain.
authors.forename: Mercedes
authors.identifier: 0000-0001-6146-996X
authors.initials: M
authors.lastname: Costell
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D005353:Fibronectins / Q000378:metabolism*; D006470:Hemorrhage; D016023:Integrins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D013927:Thrombosis / Q000378:metabolism
chemical_list: D005353:Fibronectins; D016023:Integrins
keywords: cell adhesion; cell biology; extracellular matrix; fibronectin; integrins; mechanosignaling; mouse