The fibronectin synergy site re-enforces cell adhesion and mediates a crosstalk between integrin classes

Author:

Benito-Jardón Maria12ORCID,Klapproth Sarah3,Gimeno-LLuch Irene12,Petzold Tobias4,Bharadwaj Mitasha5,Müller Daniel J5,Zuchtriegel Gabriele3,Reichel Christoph A36,Costell Mercedes12ORCID

Affiliation:

1. Department of Biochemistry and Molecular Biology, Universitat de València, Burjassot, Spain

2. Estructura de Recerca Interdisciplinar en Biotecnologia i Biomedicina, Universitat de València, Burjassot, Spain

3. Walter Brendel Centre of Experimental Medicine, Ludwig-Maximilians-Universität München, Munich, Germany

4. Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Munich, Germany

5. Eidgenössische Technische Hochschule Zürich, Basel, Switzerland

6. Departement of Otorhinolaryngology, Ludwig-Maximilians-Universität München, Munich, Germany

Abstract

Fibronectin (FN), a major extracellular matrix component, enables integrin-mediated cell adhesion via binding 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.

Funder

Ministerio de Economía y Competitividad

Conselleria Valenciana d'Educació i Ciència

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

Reference52 articles.

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2. Characterization of regions of fibronectin besides the arginine-glycine-aspartic acid sequence required for adhesive function of the cell-binding domain using site-directed mutagenesis;Aota;The Journal of Biological Chemistry,1991

3. The short amino acid sequence Pro-His-Ser-Arg-Asn in human fibronectin enhances cell-adhesive function;Aota;The Journal of Biological Chemistry,1994

4. An open cremaster muscle preparation for the study of blood vessels by in vivo microscopy;Baez;Microvascular Research,1973

5. Quantitative Measurements of Integrin‐Mediated Adhesion to Extracellular Matrix

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