title: Up-regulation of vascular endothelial growth factor-A by active membrane-type 1 matrix metalloproteinase through activation of Src-tyrosine kinases.
abstract: Membrane-type 1 matrix metalloproteinase (MT1-MMP) and vascular endothelial growth factor (VEGF) are two key molecules involved in pericellular proteolysis and cell proliferation during tumor growth and angiogenesis. Our previous data showed that MT1-MMP overexpression in human breast carcinoma MCF7 cells induced an up-regulation of VEGF expression. This effect was associated in vivo with accelerated tumor growth and angiogenesis. We now provide evidence that MT1-MMP overexpression specifically affected VEGF-A production and failed to influence that of other VEGF family members (VEGF, B, C, D, or PlGF) or their receptors. The up-regulation of VEGF-A by MT1-MMP was related to an increased transcriptional activation rather than to a modification of mRNA stability. It was blocked by synthetic MMP inhibitors, TIMP2, but not TIMP-1 and abolished by a partial deletion of the catalytic domain or the cytoplasmic tail of MT1-MMP. Analysis of the signal transduction mechanisms demonstrated that MT1-MMP acts through a signaling pathway involving Src tyrosine kinases. Thus, our results provide new insight into the mechanisms of action of MT1-MMP during angiogenesis and suggest that the full enzymatic activity of MT1-MMP is required for a specific up-regulation of VEGF-A through an activation of Src tyrosine kinase pathways.
authors.affiliation: Laboratory of Tumor and Development Biology University of Liège, Sart Tilman, 4000 Sart-Tilman, B-4000 Liège, Belgium.
authors.forename: Nor Eddine
authors.initials: NE
authors.lastname: Sounni
authors.forename: Christian
authors.initials: C
authors.lastname: Roghi
authors.forename: Vincent
authors.initials: V
authors.lastname: Chabottaux
authors.forename: Mathias
authors.initials: M
authors.lastname: Janssen
authors.forename: Carine
authors.initials: C
authors.lastname: Munaut
authors.forename: Erik
authors.initials: E
authors.lastname: Maquoi
authors.forename: Beatriz G
authors.initials: BG
authors.lastname: Galvez
authors.forename: Christine
authors.initials: C
authors.lastname: Gilles
authors.forename: Francis
authors.initials: F
authors.lastname: Frankenne
authors.forename: Gillian
authors.initials: G
authors.lastname: Murphy
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Foidart
authors.forename: Agnès
authors.initials: A
authors.lastname: Noel
mesh_terms: D000595:Amino Acid Sequence; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D015870:Gene Expression; D006801:Humans; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000737:chemistry / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000378:metabolism; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D019061:src-Family Kinases; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases