title: The protease MT1-MMP drives a combinatorial proteolytic program in activated endothelial cells.
abstract: The mechanism by which proteolytic events translate into biological responses is not well understood. To explore the link of pericellular proteolysis to events relevant to capillary sprouting within the inflammatory context, we aimed at the identification of the collection of substrates of the protease MT1-MMP in endothelial tip cells induced by inflammatory stimuli. We applied quantitative proteomics to endothelial cells (ECs) derived from wild-type and MT1-MMP-null mice to identify the substrate repertoire of this protease in TNF-α-activated ECs. Bioinformatics analysis revealed a combinatorial MT1-MMP proteolytic program, in which combined rather than single substrate processing would determine biological decisions by activated ECs, including chemotaxis, cell motility and adhesion, and vasculature development. MT1-MMP-deficient ECs inefficiently processed several of these substrates (TSP1, CYR61, NID1, and SEM3C), validating the model. This novel concept of MT1-MMP-driven combinatorial proteolysis in angiogenesis might be extendable to proteolytic actions in other cellular contexts.
authors.affiliation: Vascular Biology Department, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Koziol
authors.forename: Pilar
authors.initials: P
authors.lastname: Gonzalo
authors.forename: Alba
authors.initials: A
authors.lastname: Mota
authors.forename: Ángela
authors.initials: Á
authors.lastname: Pollán
authors.forename: Cristina
authors.initials: C
authors.lastname: Lorenzo
authors.forename: Nuria
authors.initials: N
authors.lastname: Colomé
authors.forename: David
authors.initials: D
authors.lastname: Montaner
authors.forename: Joaquín
authors.initials: J
authors.lastname: Dopazo
authors.forename: Joaquín
authors.initials: J
authors.lastname: Arribas
authors.forename: Francesc
authors.initials: F
authors.lastname: Canals
authors.forename: Alicia G
authors.initials: AG
authors.lastname: Arroyo
mesh_terms: D000818:Animals; D015153:Blotting, Western; D020650:Combinatorial Chemistry Techniques; D019295:Computational Biology; D042783:Endothelial Cells / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D007249:Inflammation; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D040081:Protein Array Analysis; D034622:RNA Interference; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D059467:Transcriptome; D014409:Tumor Necrosis Factor-alpha
chemical_list: C507096:Mmp14 protein, mouse; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D053511:Matrix Metalloproteinase 14