A1 Refereed original research article in a scientific journal
Co-chaperones TIMP2 and AHA1 Competitively Regulate Extracellular HSP90:Client MMP2 Activity and Matrix Proteolysis
Authors: Baker-Williams AJ, Hashmi F, Nski MAB, 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, Bourboulia D
Publisher: CELL PRESS
Publication year: 2019
Journal: Cell Reports
Journal name in source: CELL REPORTS
Journal acronym: CELL REP
Volume: 28
Issue: 7
First page : 1894
Number of pages: 19
ISSN: 2211-1247
DOI: https://doi.org/10.1016/j.celrep.2019.07.045
Web address : https://doi.org/10.1016/j.celrep.2019.07.045
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/41893633
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.
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