title: Membrane-type matrix metalloproteases as diverse effectors of cancer progression.
abstract: Membrane-type matrix metalloproteases (MT-MMP) are pivotal regulators of cell invasion, growth and survival. Tethered to the cell membranes by a transmembrane domain or GPI-anchor, the six MT-MMPs can exert these functions via cell surface-associated extracellular matrix degradation or proteolytic protein processing, including shedding or release of signaling receptors, adhesion molecules, growth factors and other pericellular proteins. By interactions with signaling scaffold or cytoskeleton, the C-terminal cytoplasmic tail of the transmembrane MT-MMPs further extends their functionality to signaling or structural relay. MT-MMPs are differentially expressed in cancer. The most extensively studied MMP14/MT1-MMP is induced in various cancers along malignant transformation via pathways activated by mutations in tumor suppressors or proto-oncogenes and changes in tumor microenvironment including cellular heterogeneity, extracellular matrix composition, tissue oxygenation, and inflammation. Classically such induction involves transcriptional programs related to epithelial-to-mesenchymal transition. Besides inhibition by endogenous tissue inhibitors, MT-MMP activities are spatially and timely regulated at multiple levels by microtubular vesicular trafficking, dimerization/oligomerization, other interactions and localization in the actin-based invadosomes, in both tumor and the stroma. The functions of MT-MMPs are multifaceted within reciprocal cellular responses in the evolving tumor microenvironment, which poses the importance of these proteases beyond the central function as matrix scissors, and necessitates us to rethink MT-MMPs as dynamic signaling proteases of cancer. This article is part of a Special Issue entitled: Matrix Metalloproteinases edited by Rafael Fridman.
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Nobels väg 16, SE-17177 Stockholm, Sweden.
authors.forename: S Pauliina
authors.initials: SP
authors.lastname: Turunen
authors.affiliation: Research Programs Unit, Genome-Scale Biology and Haartman Institute, University of Helsinki, and Helsinki University Hospital, P.O. Box 63, FI-00014 Helsinki, Finland.
authors.forename: Olga
authors.initials: O
authors.lastname: Tatti-Bugaeva
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Nobels väg 16, SE-17177 Stockholm, Sweden; Research Programs Unit, Genome-Scale Biology and Haartman Institute, University of Helsinki, and Helsinki University Hospital, P.O. Box 63, FI-00014 Helsinki, Finland; K. Albin Johansson Foundation, Finnish Cancer Institute, P.O. Box 63, FI-00014, Helsinki, Finland. Electronic address: kaisa.lehti@ki.se.
authors.forename: Kaisa
authors.initials: K
authors.lastname: Lehti
mesh_terms: D000818:Animals; D058750:Epithelial-Mesenchymal Transition; D058851:GPI-Linked Proteins / Q000378:metabolism*; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000378:metabolism*; D009369:Neoplasms / Q000201:enzymology* / Q000473:pathology; D009844:Oligosaccharides / Q000378:metabolism; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism
chemical_list: C559297:(6-O-aminoethylphosphonato-mannopyranosyl)-(1-2)-mannopyranosyl-(1-6)-mannopyranosyl-(1-4)-(2-amino-2-deoxyglucopyranosyl)-(1-6)-1-O-(1,2-di-O-octadecanoyl-sn-glyceryl-phosphonato)-myo-inositol; D058851:GPI-Linked Proteins; D009363:Neoplasm Proteins; D009844:Oligosaccharides; D019714:Tissue Inhibitor of Metalloproteinases; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14
keywords: EMT; Membrane-type matrix metalloprotease; cancer invasion; extracellular matrix; proteolysis; tumor microenvironment