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 β1 and αv integrins, which increased three- to fourfold during apoptosis and is dependent upon integrin β1 levels and activation state. Both enforced activation of β1 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.
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Abbreviations
- ECM:
-
extracellular matrix
- FACS®:
-
fluorescence-activated cell sorting
- GFs:
-
growth factors
- HUVECs:
-
human umbilical vein endothelial cells
- MMPs:
-
matrix metalloproteinases
- MT-MMPs:
-
membrane-type matrix metalloproteinases
- TIMPs:
-
tissue inhibitors of metalloproteinases
- TNFα:
-
tumor necrosis factor α
- uPA:
-
urokinase-type plasminogen activator
- VEGF:
-
vascular endothelial growth factor
- ZVAD-fmk:
-
benzoyloxycarbonyl1-Val-Ala-Asp fluoromethyl ketone
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Acknowledgements
The authors thank Li-Chuan Huang for technical assistance, Jingjing Tang for assistance with the FACS® analysis, and Barbara Droker for editorial assistance. This work was supported by the National Institutes of Health grants HL18645 (R Ross, EW Raines, AW Clowes) and HL30946 (AW Clowes, RD Kenagy), the Canadian Institutes of Health Research grant MOP 37938 (A Karsan), and the Interdisziplinäres Zentrum für Klinische Forschung (IZKF-11), Münster (B Levkau).
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Levkau, B., Kenagy, R., Karsan, A. et al. Activation of metalloproteinases and their association with integrins: an auxiliary apoptotic pathway in human endothelial cells. Cell Death Differ 9, 1360–1367 (2002). https://doi.org/10.1038/sj.cdd.4401106
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DOI: https://doi.org/10.1038/sj.cdd.4401106
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