Activation of metalloproteinases and their association with integrins: an auxiliary apoptotic pathway in human endothelial cells.
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.
Levkau
B
B
Department of Pathology, University of Washington, Seattle, WA, USA.
Kenagy
R D
RD
Karsan
A
A
Weitkamp
B
B
Clowes
A W
AW
Ross
R
R
Raines
E W
EW
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005109:Extracellular Matrix / Q000201:enzymology*; D006801:Humans; D039564:Integrin alphaV / Q000187:drug effects / Q000378:metabolism; D019012:Integrin beta1 / Q000187:drug effects / Q000378:metabolism; D016023:Integrins / Q000187:drug effects / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000187:drug effects / Q000378:metabolism; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051419:Paxillin; D010750:Phosphoproteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D003598:Cytoskeletal Proteins; D004791:Enzyme Inhibitors; D039564:Integrin alphaV; D019012:Integrin beta1; D016023:Integrins; C496061:PXN protein, human; D051419:Paxillin; D010750:Phosphoproteins; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2