Co-chaperones TIMP2 and AHA1 Competitively Regulate Extracellular HSP90:Client MMP2 Activity and Matrix Proteolysis
Makedon AM; Bratslavsky G; Friedman D; Himanen SV; Namek S; Woodford MR; Mollapour M; Nski MAB; Gleicher S; Sistonen L; Bourboulia D; Bah A; Stetler-Stevenson WG; Cortes S; Hashmi F; Baker-Williams AJ
Co-chaperones TIMP2 and AHA1 Competitively Regulate Extracellular HSP90:Client MMP2 Activity and Matrix Proteolysis
Makedon AM
Bratslavsky G
Friedman D
Himanen SV
Namek S
Woodford MR
Mollapour M
Nski MAB
Gleicher S
Sistonen L
Bourboulia D
Bah A
Stetler-Stevenson WG
Cortes S
Hashmi F
Baker-Williams AJ
CELL PRESS
Julkaisun pysyvä osoite on:
https://urn.fi/URN:NBN:fi-fe2021042827580
https://urn.fi/URN:NBN:fi-fe2021042827580
Tiivistelmä
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.
Kokoelmat
- Rinnakkaistallenteet [19207]