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.
Original language | English |
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Pages (from-to) | 1894-1906.e6 |
Journal | Cell Reports |
Volume | 28 |
Issue number | 7 |
DOIs | |
Publication status | Published - 13 Aug 2019 |
MoE publication type | A1 Journal article-refereed |
Keywords
- Animals
- Cells, Cultured
- Extracellular Matrix/metabolism
- Fibroblasts/cytology
- HEK293 Cells
- HSP90 Heat-Shock Proteins/genetics
- Humans
- Matrix Metalloproteinase 2/genetics
- Mice
- Mice, Knockout
- Molecular Chaperones/genetics
- Proteolysis
- Tissue Inhibitor of Metalloproteinase-2/genetics