期刊
CELL REPORTS
卷 28, 期 7, 页码 1894-+出版社
CELL PRESS
DOI: 10.1016/j.celrep.2019.07.045
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资金
- Abo Akademi University
- Academy of Finland
- Sigrid Juselius Foundation
- Magnus Ehrnrooth Foundation
- Cancer Foundation Finland
- SUNY Upstate Medical University
- Upstate Foundation
- SUNY Research Foundation
- Upstate Breast Cancer Research funds
- Carol M. Baldwin Breast Cancer Research Fund grant
- Associated Medical Schools of New York
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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