Integrins are the major family of cell surface adhesion receptors responsible for the regulation of the physical contact and biochemical communication between the cell and the surrounding extracellular matrix (ECM). Binding of the extracellular domains of integrins to components in the ECM triggers a series of molecular events commonly referred to as “outside-in” signaling, leading to context-dependent changes in cell morphology, migration and proliferation. In this prevailing paradigm of cell adhesion induced signaling the primary functions of the integrin is to provide the physical transmembrane bridge connecting the intracellular signaling machinery and cytoskeleton to the extracellular environment. We now present evidence that most, if not all, cell adhesion receptors trigger integrin-dependent outside-in signaling independently of direct contacts between the integrins and their ligands in the ECM. The urokinase-type plasminogen activator receptor (uPAR/CD87) is a non-integrin vitronectin (VN) cell adhesion receptor linked to the outer membrane leaflet by a GPI-anchor. Through an extensive structure-function analysis of uPAR, VN, β1 and β3 we document that cell adhesion induced by the uPAR/VN-interaction triggers integrin-mediated, but ligand independent, cell spreading and signaling. This signaling is fully active on VN lacking functional integrin binding sites and by integrin mutants deficient in ligand binding, but is crucially dependent on an “active” conformation of the integrin as well as its binding to intracellular adaptor proteins including talin and kindlin. This novel paradigm of ligand-independent integrin signaling is not restricted to uPAR as it poses no identifiable constraints to the adhesion receptor with respect to ternary-structure, ligand type or means of membrane anchorage. In full accordance with a general validity of this paradigm, we show that cell adhesion physically mediated by a signaling-incompetent β3 integrin is effectively translated into cell spreading and signaling by the β1 integrin. Our results show that integrins are active in transducing adhesion-induced signaling in the absence of their cognate ligands, suggesting that the bi-directional signaling capability of these receptors may have evolved primarily to allow for tightly regulated inside-out signaling.
NON-INTEGRIN CELL ADHESION TRIGGERS LIGAND-INDEPENDENT INTEGRIN SIGNALING / G.m. Sarra Ferraris ; Supervisor: Nicolai Sidenius. - Milano : Università degli studi di Milano. Universita' degli Studi di Milano, 2011 Mar 02. ((22. ciclo, Anno Accademico 2010.
|Titolo:||NON-INTEGRIN CELL ADHESION TRIGGERS LIGAND-INDEPENDENT INTEGRIN SIGNALING|
|Tutor esterno:||SIDENIUS, NICOLAI|
|Data di pubblicazione:||2-mar-2011|
|Parole Chiave:||integrin ; uPAR ; cell adhesion ; cell migration|
|Settore Scientifico Disciplinare:||Settore BIO/10 - Biochimica|
|Citazione:||NON-INTEGRIN CELL ADHESION TRIGGERS LIGAND-INDEPENDENT INTEGRIN SIGNALING / G.m. Sarra Ferraris ; Supervisor: Nicolai Sidenius. - Milano : Università degli studi di Milano. Universita' degli Studi di Milano, 2011 Mar 02. ((22. ciclo, Anno Accademico 2010.|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.13130/sarra-ferraris-gianni-maria_phd2011-03-02|
|Appare nelle tipologie:||Tesi di dottorato|