title: RhoB regulates uPAR signalling.
abstract: Urokinase-type plasminogen activator (uPA) and its receptor, uPAR, play important roles in promoting cancer cell adhesion, migration and invasion. Rho GTPases are key coordinators of these processes; the Rho GTPase Rac1 has previously been implicated in uPA- and/or uPAR-induced migratory or morphological cell responses. We used RNAi to deplete 12 different Rho GTPases to screen for effects on uPA-stimulated migration, and found that depletion of RhoB significantly reduces uPA-induced migration and invasion of prostate carcinoma cells. RhoB depletion did not affect the expression or surface levels of uPAR but reduced the uPAR-induced increase in levels of several integrins and inhibited uPAR signalling to the actin regulator cofilin, the cell-adhesion signal-transduction adaptor molecule paxillin and the serine/threonine kinase Akt. uPAR rapidly activated RhoB and increased RhoB expression. RhoB depletion also reduced cell adhesion to and spreading on vitronectin, which is a uPAR ligand. This correlated with decreased association between integrins and uPAR and reduced integrin β1 activity. Our results indicate that RhoB is a key regulator of uPAR signalling in cell adhesion, migration and invasion.
authors.affiliation: Randall Division of Cell and Molecular Biophysics, King's College London, New Hunt's House, Guy's Campus, London, UK.
authors.forename: Daniela
authors.initials: D
authors.lastname: Alfano
authors.forename: Pia
authors.initials: P
authors.lastname: Ragno
authors.forename: M Patrizia
authors.initials: MP
authors.lastname: Stoppelli
authors.forename: Anne J
authors.initials: AJ
authors.lastname: Ridley
mesh_terms: D002448:Cell Adhesion; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D006801:Humans; D016023:Integrins / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism*; D019096:Vitronectin / Q000378:metabolism; D020743:rhoB GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D016023:Integrins; D055293:Receptors, Urokinase Plasminogen Activator; D019096:Vitronectin; D014568:Urokinase-Type Plasminogen Activator; D020743:rhoB GTP-Binding Protein