TIMP-1 inhibits microvascular endothelial cell migration by MMP-dependent and MMP-independent mechanisms. 2004

Takemi Akahane, and Manabu Akahane, and Amy Shah, and Christine M Connor, and Unnur P Thorgeirsson
Laboratory of Cellular Carcinogenesis and Tumor Promotion, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4255, USA.

It was reported over a decade ago that tissue inhibitor of metalloproteinases-1 (TIMP-1) suppresses angiogenesis in experimental models but the mechanism is still incompletely understood. This in vitro study focused on the molecular basis of TIMP-1-mediated inhibition of endothelial cell (EC) migration, a key step in the angiogenic process. Both recombinant human TIMP-1 and the synthetic MMP inhibitors, GM6001 and MMP-2-MMP-9 Inhibitor III, suppressed migration of human dermal microvascular endothelial cells (HDMVEC) in a dose-dependent fashion. The MMP-dependent inhibition of migration was associated with increased expression of the junctional adhesion proteins, VE-cadherin and PECAM-1, and VE-cadherin accumulation at cell-cell junctions. TIMP-1 also caused MMP-independent dephosphorylation of focal adhesion kinase (FAK) (pY397) and paxillin, which was associated with reduced number of F-actin stress fibers and focal adhesions. Moreover, TIMP-1 stimulated expression of PTEN that has been shown to reduce phosphorylation of FAK and inhibit cell migration. Our data suggest that TIMP-1 inhibits HDMVEC migration through MMP-dependent stimulation of VE-cadherin and MMP-independent stimulation of PTEN with subsequent dephosphorylation of FAK and cytoskeletal remodeling.

UI MeSH Term Description Entries
D008833 Microcirculation The circulation of the BLOOD through the MICROVASCULAR NETWORK. Microvascular Blood Flow,Microvascular Circulation,Blood Flow, Microvascular,Circulation, Microvascular,Flow, Microvascular Blood,Microvascular Blood Flows,Microvascular Circulations
D010744 Phosphoric Monoester Hydrolases A group of hydrolases which catalyze the hydrolysis of monophosphoric esters with the production of one mole of orthophosphate. Phosphatase,Phosphatases,Phosphohydrolase,Phosphohydrolases,Phosphomonoesterase,Phosphomonoesterases,Phosphoric Monoester Hydrolase,Hydrolase, Phosphoric Monoester,Hydrolases, Phosphoric Monoester,Monoester Hydrolase, Phosphoric
D010766 Phosphorylation The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. Phosphorylations
D011505 Protein-Tyrosine Kinases Protein kinases that catalyze the PHOSPHORYLATION of TYROSINE residues in proteins with ATP or other nucleotides as phosphate donors. Tyrosine Protein Kinase,Tyrosine-Specific Protein Kinase,Protein-Tyrosine Kinase,Tyrosine Kinase,Tyrosine Protein Kinases,Tyrosine-Specific Protein Kinases,Tyrosylprotein Kinase,Kinase, Protein-Tyrosine,Kinase, Tyrosine,Kinase, Tyrosine Protein,Kinase, Tyrosine-Specific Protein,Kinase, Tyrosylprotein,Kinases, Protein-Tyrosine,Kinases, Tyrosine Protein,Kinases, Tyrosine-Specific Protein,Protein Kinase, Tyrosine-Specific,Protein Kinases, Tyrosine,Protein Kinases, Tyrosine-Specific,Protein Tyrosine Kinase,Protein Tyrosine Kinases,Tyrosine Specific Protein Kinase,Tyrosine Specific Protein Kinases
D002478 Cells, Cultured Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others. Cultured Cells,Cell, Cultured,Cultured Cell
D002633 Chemotaxis The movement of cells or organisms toward or away from a substance in response to its concentration gradient. Haptotaxis
D003599 Cytoskeleton The network of filaments, tubules, and interconnecting filamentous bridges which give shape, structure, and organization to the cytoplasm. Cytoplasmic Filaments,Cytoskeletal Filaments,Microtrabecular Lattice,Cytoplasmic Filament,Cytoskeletal Filament,Cytoskeletons,Filament, Cytoplasmic,Filament, Cytoskeletal,Filaments, Cytoplasmic,Filaments, Cytoskeletal,Lattice, Microtrabecular,Lattices, Microtrabecular,Microtrabecular Lattices
D004305 Dose-Response Relationship, Drug The relationship between the dose of an administered drug and the response of the organism to the drug. Dose Response Relationship, Drug,Dose-Response Relationships, Drug,Drug Dose-Response Relationship,Drug Dose-Response Relationships,Relationship, Drug Dose-Response,Relationships, Drug Dose-Response
D004730 Endothelium, Vascular Single pavement layer of cells which line the luminal surface of the entire vascular system and regulate the transport of macromolecules and blood components. Capillary Endothelium,Vascular Endothelium,Capillary Endotheliums,Endothelium, Capillary,Endotheliums, Capillary,Endotheliums, Vascular,Vascular Endotheliums
D004791 Enzyme Inhibitors Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. Enzyme Inhibitor,Inhibitor, Enzyme,Inhibitors, Enzyme

Related Publications

Takemi Akahane, and Manabu Akahane, and Amy Shah, and Christine M Connor, and Unnur P Thorgeirsson
April 1996, Molecular and cellular neurosciences,
Takemi Akahane, and Manabu Akahane, and Amy Shah, and Christine M Connor, and Unnur P Thorgeirsson
December 1997, The American journal of pathology,
Takemi Akahane, and Manabu Akahane, and Amy Shah, and Christine M Connor, and Unnur P Thorgeirsson
February 2014, Cancer letters,
Takemi Akahane, and Manabu Akahane, and Amy Shah, and Christine M Connor, and Unnur P Thorgeirsson
March 2010, Cornea,
Takemi Akahane, and Manabu Akahane, and Amy Shah, and Christine M Connor, and Unnur P Thorgeirsson
January 2019, Frontiers in molecular neuroscience,
Takemi Akahane, and Manabu Akahane, and Amy Shah, and Christine M Connor, and Unnur P Thorgeirsson
June 2002, Molecular biology of the cell,
Takemi Akahane, and Manabu Akahane, and Amy Shah, and Christine M Connor, and Unnur P Thorgeirsson
June 2019, Biochemical Society transactions,
Takemi Akahane, and Manabu Akahane, and Amy Shah, and Christine M Connor, and Unnur P Thorgeirsson
January 2011, Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer,
Takemi Akahane, and Manabu Akahane, and Amy Shah, and Christine M Connor, and Unnur P Thorgeirsson
March 2008, Cancer letters,
Takemi Akahane, and Manabu Akahane, and Amy Shah, and Christine M Connor, and Unnur P Thorgeirsson
March 2001, Cardiovascular research,
Copied contents to your clipboard!