title: Podoplanin mediates ECM degradation by squamous carcinoma cells through control of invadopodia stability.
abstract: Invadopodia are actin-rich cell membrane projections used by invasive cells to penetrate the basement membrane. Control of invadopodia stability is critical for efficient degradation of the extracellular matrix (ECM); however, the underlying molecular mechanisms remain poorly understood. Here, we uncover a new role for podoplanin, a transmembrane glycoprotein closely associated with malignant progression of squamous cell carcinomas (SCCs), in the regulation of invadopodia-mediated matrix degradation. Podoplanin downregulation in SCC cells impairs invadopodia stability, thereby reducing the efficiency of ECM degradation. We report podoplanin as a novel component of invadopodia-associated adhesion rings, where it clusters prior to matrix degradation. Early podoplanin recruitment to invadopodia is dependent on lipid rafts, whereas ezrin/moesin proteins mediate podoplanin ring assembly. Finally, we demonstrate that podoplanin regulates invadopodia maturation by acting upstream of the ROCK-LIMK-Cofilin pathway through the control of RhoC GTPase activity. Thus, podoplanin has a key role in the regulation of invadopodia function in SCC cells, controlling the initial steps of cancer cell invasion.
authors.affiliation: Instituto de Investigaciones Biomédicas 'Alberto Sols' (CSIC-UAM), Madrid, Spain.|Randall Division of Cell & Molecular Biophysics, King's College London, London, UK.
authors.forename: E
authors.initials: E
authors.lastname: Martín-Villar
authors.affiliation: Randall Division of Cell & Molecular Biophysics, King's College London, London, UK.
authors.forename: B
authors.initials: B
authors.lastname: Borda-d'Agua
authors.affiliation: Instituto de Investigaciones Biomédicas 'Alberto Sols' (CSIC-UAM), Madrid, Spain.
authors.forename: P
authors.initials: P
authors.lastname: Carrasco-Ramirez
authors.affiliation: Instituto de Investigaciones Biomédicas 'Alberto Sols' (CSIC-UAM), Madrid, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Renart
authors.affiliation: Randall Division of Cell & Molecular Biophysics, King's College London, London, UK.
authors.forename: M
authors.initials: M
authors.lastname: Parsons
authors.affiliation: Instituto de Investigaciones Biomédicas 'Alberto Sols' (CSIC-UAM), Madrid, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Quintanilla
authors.affiliation: Randall Division of Cell & Molecular Biophysics, King's College London, London, UK.
authors.forename: G E
authors.initials: GE
authors.lastname: Jones
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D022081:Cell Surface Extensions / Q000502:physiology*; D005109:Extracellular Matrix / Q000378:metabolism*; D006801:Humans; D054461:Lim Kinases / Q000502:physiology; D008562:Membrane Glycoproteins / Q000502:physiology*; D021962:Membrane Microdomains / Q000502:physiology; D015398:Signal Transduction; D020741:rho GTP-Binding Proteins / Q000502:physiology; D054460:rho-Associated Kinases / Q000502:physiology; D000075024:rhoC GTP-Binding Protein; D000098853:Podoplanin
chemical_list: D054461:Lim Kinases; D008562:Membrane Glycoproteins; D020741:rho GTP-Binding Proteins; D054460:rho-Associated Kinases; D000075024:rhoC GTP-Binding Protein; C117468:PDPN protein, human; D000098853:Podoplanin; C515892:LIMK1 protein, human; C066690:RHOC protein, human