Abstract
Anchorage of cells to the extracellular matrix and integrin-mediated signals play crucial roles in cell survival. We have previously shown that during growth factor deprivation-induced apoptosis in human umbilical vein endothelial cells (HUVECs), key molecules in focal adhesions and adherens junctions are cleaved by caspases. In this study we provide evidence for a selective upregulation of cell-associated matrix metalloproteinases (MMPs). We observe a physical association of MMP2 with beta1 and alphav integrins, which increased three- to fourfold during apoptosis and is dependent upon integrin beta1 levels and activation state. Both enforced activation of beta1 integrin by a specific antibody and inhibition of MMPs protect HUVECs from apoptosis. We hypothesize that, prior to the commitment to apoptosis, 'inside-out' signals initiated by the apoptotic stimulus alter cell shape together with the activation states and/or the availability of integrins, which promote matrix-degrading activity around dying cells. This 'auxiliary' apoptotic pathway may interrupt ECM-mediated survival signaling, and thus accelerate the efficient execution of the cell death program.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Apoptosis / drug effects
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Apoptosis / physiology*
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Cell Adhesion / drug effects
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Cell Adhesion / physiology*
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Cell Survival / drug effects
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Cell Survival / physiology*
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Cells, Cultured
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Cytoskeletal Proteins / metabolism
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Endothelium, Vascular / cytology
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Endothelium, Vascular / drug effects
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Endothelium, Vascular / enzymology*
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Enzyme Inhibitors / pharmacology
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Extracellular Matrix / enzymology*
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Humans
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Integrin alphaV / drug effects
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Integrin alphaV / metabolism
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Integrin beta1 / drug effects
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Integrin beta1 / metabolism
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Integrins / drug effects
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Integrins / metabolism*
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Matrix Metalloproteinase 2 / drug effects
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Matrix Metalloproteinase 2 / metabolism
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Matrix Metalloproteinases, Membrane-Associated
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Metalloendopeptidases / antagonists & inhibitors
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Metalloendopeptidases / metabolism*
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Paxillin
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Phosphoproteins / metabolism
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Signal Transduction / drug effects
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Signal Transduction / physiology
Substances
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Cytoskeletal Proteins
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Enzyme Inhibitors
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Integrin alphaV
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Integrin beta1
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Integrins
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PXN protein, human
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Paxillin
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Phosphoproteins
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Matrix Metalloproteinases, Membrane-Associated
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Metalloendopeptidases
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Matrix Metalloproteinase 2