title: The interaction between uPAR and vitronectin triggers ligand-independent adhesion signalling by integrins.
abstract: The urokinase-type plasminogen activator receptor (uPAR) is a non-integrin vitronectin (VN) cell adhesion receptor linked to the plasma membrane by a glycolipid anchor. Through structure-function analyses of uPAR, VN and integrins, we document that uPAR-mediated cell adhesion to VN triggers a novel type of integrin signalling that is independent of integrin-matrix engagement. The signalling is fully active on VN mutants deficient in integrin binding site and is also efficiently transduced by integrins deficient in ligand binding. Although integrin ligation is dispensable, signalling is crucially dependent upon an active conformation of the integrin and its association with intracellular adaptors such as talin. This non-canonical integrin signalling is not restricted to uPAR as it poses no structural constraints to the receptor mediating cell attachment. In contrast to canonical integrin signalling, where integrins form direct mechanical links between the ECM and the cytoskeleton, the molecular mechanism enabling the crosstalk between non-integrin adhesion receptors and integrins is dependent upon membrane tension. This suggests that for this type of signalling, the membrane represents a critical component of the molecular clutch.
authors.affiliation: Unit of Cell Matrix Signalling, IFOM the FIRC Institute of Molecular Oncology, Milan, Italy.
authors.forename: Gian Maria Sarra
authors.initials: GM
authors.lastname: Ferraris
authors.affiliation: Unit of Cell Matrix Signalling, IFOM the FIRC Institute of Molecular Oncology, Milan, Italy Interdisciplinary Centre for Nanostructured Materials and Interfaces (CIMaINa), University of Milan, Milan, Italy.
authors.forename: Carsten
authors.initials: C
authors.lastname: Schulte
authors.affiliation: Unit of Cell Matrix Signalling, IFOM the FIRC Institute of Molecular Oncology, Milan, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Buttiglione
authors.affiliation: Unit of Cell Matrix Signalling, IFOM the FIRC Institute of Molecular Oncology, Milan, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: De Lorenzi
authors.affiliation: Unit of Cell Matrix Signalling, IFOM the FIRC Institute of Molecular Oncology, Milan, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Piontini
authors.affiliation: Interdisciplinary Centre for Nanostructured Materials and Interfaces (CIMaINa), University of Milan, Milan, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Galluzzi
authors.affiliation: Interdisciplinary Centre for Nanostructured Materials and Interfaces (CIMaINa), University of Milan, Milan, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Podestà
authors.affiliation: Unit of Cell Matrix Signalling, IFOM the FIRC Institute of Molecular Oncology, Milan, Italy.
authors.forename: Chris D
authors.initials: CD
authors.lastname: Madsen
authors.affiliation: Unit of Cell Matrix Signalling, IFOM the FIRC Institute of Molecular Oncology, Milan, Italy nicolai.sidenius@ifom.eu.
authors.forename: Nicolai
authors.initials: N
authors.lastname: Sidenius
mesh_terms: D002448:Cell Adhesion / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D016023:Integrins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D055293:Receptors, Urokinase Plasminogen Activator / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D019096:Vitronectin / Q000235:genetics / Q000378:metabolism*
chemical_list: D016023:Integrins; D055293:Receptors, Urokinase Plasminogen Activator; D019096:Vitronectin
keywords: integrin; membrane tension; signalling; uPAR; vitronectin