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Co-chaperones TIMP2 and AHA1 Competitively Regulate Extracellular HSP90:Client MMP2 Activity and Matrix Proteolysis.
- Source :
-
Cell reports [Cell Rep] 2019 Aug 13; Vol. 28 (7), pp. 1894-1906.e6. - Publication Year :
- 2019
-
Abstract
- The extracellular molecular chaperone heat shock protein 90 (eHSP90) stabilizes protease client the matrix metalloproteinase 2 (MMP2), leading to tumor cell invasion. Although co-chaperones are critical modulators of intracellular HSP90:client function, how the eHSP90:MMP2 complex is regulated remains speculative. Here, we report that the tissue inhibitor of metalloproteinases-2 (TIMP2) is a stress-inducible extracellular co-chaperone that binds to eHSP90, increases eHSP90 binding to ATP, and inhibits its ATPase activity. In addition to disrupting the eHSP90:MMP2 complex and terminally inactivating MMP2, TIMP2 loads the client to eHSP90, keeping the protease in a transient inhibitory state. Secreted activating co-chaperone AHA1 displaces TIMP2 from the complex, providing a "reactivating" mechanism for MMP2. Gene knockout or blocking antibodies targeting TIMP2 and AHA1 released by HT1080 cancer cells modify their gelatinolytic activity. Our data suggest that TIMP2 and AHA1 co-chaperones function as a molecular switch that determines the inhibition and reactivation of the eHSP90 client protein MMP2.<br /> (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Cells, Cultured
Fibroblasts cytology
Fibroblasts metabolism
HEK293 Cells
HSP90 Heat-Shock Proteins genetics
Humans
Matrix Metalloproteinase 2 genetics
Mice
Mice, Knockout
Molecular Chaperones genetics
Tissue Inhibitor of Metalloproteinase-2 genetics
Extracellular Matrix metabolism
HSP90 Heat-Shock Proteins metabolism
Matrix Metalloproteinase 2 metabolism
Molecular Chaperones metabolism
Molecular Chaperones physiology
Proteolysis
Tissue Inhibitor of Metalloproteinase-2 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2211-1247
- Volume :
- 28
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Cell reports
- Publication Type :
- Academic Journal
- Accession number :
- 31412254
- Full Text :
- https://doi.org/10.1016/j.celrep.2019.07.045