TIMP-1 inhibits microvascular endothelial cell migration by MMP-dependent and MMP-independent mechanisms.
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.
Akahane
Takemi
T
Laboratory of Cellular Carcinogenesis and Tumor Promotion, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4255, USA.
Akahane
Manabu
M
Shah
Amy
A
Connor
Christine M
CM
Thorgeirsson
Unnur P
UP
D015703:Antigens, CD; D015820:Cadherins / Q000378:metabolism; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects*; D003599:Cytoskeleton / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006801:Humans; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000502:physiology*; D008833:Microcirculation; D018919:Neovascularization, Physiologic; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000494:pharmacology*; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D000099152:Cadherin 5
D015703:Antigens, CD; D015820:Cadherins; D004791:Enzyme Inhibitors; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases; D011505:Protein-Tyrosine Kinases; D019715:Tissue Inhibitor of Metalloproteinase-1; D025521:Tumor Suppressor Proteins; D000099152:Cadherin 5; C496050:PTK2 protein, human; C494929:PTEN protein, human