title: Matrix metalloproteinase 19 processes the laminin 5 gamma 2 chain and induces epithelial cell migration.
abstract: In this study we analyzed the proteolytic activity of MMP-19 and its impact on keratinocyte migration. In the HaCaT keratinocyte cell line overexpressing wild-type MMP-19 (HaCaT-WT), transmigration through fibrin and type IV collagen matrices was significantly increased compared to cells harboring a catalytically inactive mutant (HaCaT-EA). Studying the expression of MMP-19 in early stages of squamous cell cancer (SCC), we found co-localization of MMP-19 and laminin 5 at the invading tumor front but not in suprabasal epidermis of the tumor. Examination of laminin 5 processing revealed increased processing of the gamma2 chain in the medium and matrix of HaCaT-WT cells and degradation by recombinant human MMP-19 to 105-kDa and 80-kDa fragments. Parental HaCaT grown on the matrix of HaCaT-WT and HaCaT-EA cells displayed differential tyrosine phosphorylation. Using integrin blocking and stimulating antibodies we could attribute these differences to a shift from beta4-integrin-dependent signaling on the HaCaT-EA matrix toward alpha3-integrin-dependent signaling on the HaCaT-WT matrix. As a consequence, parental HaCaT showed increased migration on the matrix of HaCaT-WT cells. These data suggest that the MMP-19-dependent processing of the gamma2 chains leads to the integrin switch favoring epithelial migration and that MMP-19 actively participates in the early stages of SCC invasion.
authors.affiliation: Institute of Biochemistry, University of Kiel, Olshausenstrasse 40, 24098 Kiel, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Sadowski
authors.forename: S
authors.initials: S
authors.lastname: Dietrich
authors.forename: F
authors.initials: F
authors.lastname: Koschinsky
authors.forename: A
authors.initials: A
authors.lastname: Ludwig
authors.forename: E
authors.initials: E
authors.lastname: Proksch
authors.forename: B
authors.initials: B
authors.lastname: Titz
authors.forename: R
authors.initials: R
authors.lastname: Sedlacek
mesh_terms: D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D024141:Collagen Type IV / Q000378:metabolism; D000078404:Epidermal Cells; D004817:Epidermis / Q000378:metabolism; D005337:Fibrin / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D007797:Laminin / Q000378:metabolism*; D053505:Matrix Metalloproteinases, Secreted; D008666:Metalloendopeptidases / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D018307:Neoplasms, Squamous Cell / Q000378:metabolism* / Q000473:pathology; D019000:Phosphotyrosine / Q000378:metabolism
chemical_list: D024141:Collagen Type IV; C400567:LAMC2 protein, human; D007797:Laminin; D019000:Phosphotyrosine; D005337:Fibrin; D053505:Matrix Metalloproteinases, Secreted; D008666:Metalloendopeptidases; C108362:matrix metalloproteinase 19