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

Alexander J Baker-Williams, Fiza Hashmi, Marek A Budzyński, Mark R Woodford, Stephanie Gleicher, Samu V Himanen, Alan M Makedon, Derek Friedman, Stephanie Cortes, Sara Namek, William G Stetler-Stevenson, Gennady Bratslavsky, Alaji Bah, Mehdi Mollapour, Lea Sistonen, Dimitra Bourboulia

Research output: Contribution to journalArticleScientificpeer-review


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.

Original languageEnglish
Pages (from-to)1894-1906.e6
JournalCell Reports
Issue number7
Publication statusPublished - 13 Aug 2019
MoE publication typeA1 Journal article-refereed


  • Animals
  • Cells, Cultured
  • Extracellular Matrix/metabolism
  • Fibroblasts/cytology
  • HEK293 Cells
  • HSP90 Heat-Shock Proteins/genetics
  • Humans
  • Matrix Metalloproteinase 2/genetics
  • Mice
  • Mice, Knockout
  • Molecular Chaperones/genetics
  • Proteolysis
  • Tissue Inhibitor of Metalloproteinase-2/genetics


Dive into the research topics of 'Co-chaperones TIMP2 and AHA1 Competitively Regulate Extracellular HSP90:Client MMP2 Activity and Matrix Proteolysis'. Together they form a unique fingerprint.

Cite this