1. Co-chaperones TIMP2 and AHA1 Competitively Regulate Extracellular HSP90:Client MMP2 Activity and Matrix Proteolysis.
- Author
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Baker-Williams AJ, Hashmi F, Budzyński MA, Woodford MR, Gleicher S, Himanen SV, Makedon AM, Friedman D, Cortes S, Namek S, Stetler-Stevenson WG, Bratslavsky G, Bah A, Mollapour M, Sistonen L, and Bourboulia D
- 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
- 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., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
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