title: Membrane-type 1-matrix metalloproteinase regulates intracellular adhesion molecule-1 (ICAM-1)-mediated monocyte transmigration.
abstract: We examined the mechanism regulating intercellular cell adhesion molecule-1 (ICAM-1)-dependent monocyte transendothelial migration. Monocyte migration through endothelial cells expressing ICAM-1 alone was comparable to that of tumor necrosis factor-alpha-treated cells. Transmigration was reduced in ICAM-1 lacking the cytoplasmic tail and in tyrosine to alanine substitutions at Tyr-485 and Tyr-474. Tissue inhibitors of matrix metalloproteinases (TIMPs) -2 and -3 blocked transmigration, whereas TIMP-1 was ineffective. This profile suggested a role for membrane-type matrix metalloproteinases (MT-MMPs) in transmigration. Inhibitory antibodies and small interference RNA directed against MT1-MMP blocked transmigration, whereas overexpression of MT1-MMP in endothelial cells or monocytes promoted transmigration. MT1-MMP mediated the ectodomain cleavage of ICAM-1 that was blocked by TIMP-2 and -3. Overexpression of MT1-MMP rescued function in ICAM-1Y485A, and to a lesser extent in the cytoplasmic tail-deleted ICAM-1. In a binding assay, wild-type ICAM-1 bound to purified MT1-MMP while ICAM-1 mutants bound poorly. MT1-MMP co-localized with ICAM-1 at distinct structures in endothelial cells. MT1-MMP localization with cells expressing ICAM-1 mutations was reduced and diffused. These results indicate that the cytoplasmic tail of ICAM-1 regulates leukocyte transmigration through MT1-MMP interaction.
authors.affiliation: Department of Physiology and Biophysics, University of Louisville, Louisville, Kentucky 40202, USA.
authors.forename: Srinivas D
authors.initials: SD
authors.lastname: Sithu
authors.forename: William R
authors.initials: WR
authors.lastname: English
authors.forename: Paul
authors.initials: P
authors.lastname: Olson
authors.forename: Davia
authors.initials: D
authors.lastname: Krubasik
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Baker
authors.forename: Gillian
authors.initials: G
authors.lastname: Murphy
authors.forename: Stanley E
authors.initials: SE
authors.lastname: D'Souza
mesh_terms: D000256:Adenoviridae / Q000378:metabolism; D001011:Aorta / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement; D003593:Cytoplasm / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology; D005786:Gene Expression Regulation; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis*; D007962:Leukocytes / Q000378:metabolism; D053511:Matrix Metalloproteinase 14 / Q000502:physiology*; D008954:Models, Biological; D009000:Monocytes / Q000378:metabolism*; D009154:Mutation; D011485:Protein Binding
chemical_list: D018799:Intercellular Adhesion Molecule-1; D053511:Matrix Metalloproteinase 14