Co-chaperones TIMP2 and AHA1 Competitively Regulate Extracellular HSP90:Client MMP2 Activity and Matrix Proteolysis

Area of Science:

• Molecular Biology
• Cancer Research
• Biochemistry

Background:

• Extracellular heat shock protein 90 (eHSP90) stabilizes matrix metalloproteinase 2 (MMP2), promoting tumor cell invasion.
• Regulation of the eHSP90:MMP2 complex by extracellular co-chaperones is not well understood.

Purpose of the Study:

• To investigate the role of extracellular co-chaperones in regulating the eHSP90:MMP2 complex.
• To elucidate the mechanism by which TIMP2 and AHA1 modulate MMP2 activity.

Main Methods:

• Investigated the interaction between TIMP2 and eHSP90.
• Assessed the effect of TIMP2 on eHSP90 ATPase activity.
• Utilized gene knockout and blocking antibodies in HT1080 cancer cells to study TIMP2 and AHA1 function.

Main Results:

• Identified TIMP2 as a stress-inducible extracellular co-chaperone that binds eHSP90, increasing ATP binding and inhibiting ATPase activity.
• TIMP2 disrupts the eHSP90:MMP2 complex, inactivates MMP2, and maintains it in a transient inhibitory state.
• AHA1 displaces TIMP2, reactivating MMP2, with gene knockouts/blocking antibodies affecting cancer cell gelatinolytic activity.

Conclusions:

• TIMP2 and AHA1 function as a molecular switch controlling the inhibition and reactivation of the eHSP90 client protein MMP2.
• This regulatory mechanism is crucial for modulating MMP2 activity in the extracellular environment.
• Findings provide insights into novel therapeutic targets for cancer invasion.