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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.
This article was published in the following journal.
Name: Cell reports
Hsp90 is an essential chaperone that requires large allosteric changes to determine its ATPase activity and client binding. The co-chaperone Aha1, which is the major ATPase stimulator in eukaryotes, i...
HSP90 is a molecular chaperone that increases the stability of client proteins. Cancer cells show higher HSP90 expression than normal cells because many client proteins play an important role in the g...
The molecular chaperone Hsp90 stabilizes and activates client proteins. Co-chaperones and post-translational modifications tightly regulate Hsp90 function and consequently lead to activation of clien...
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A class of MOLECULAR CHAPERONES whose members act in the mechanism of SIGNAL TRANSDUCTION by STEROID RECEPTORS.
A procedure in which the therapist refrains from directing the client, but instead reflects back to the client what the latter has said, sometimes restating the client's remark.
A nondirective psychotherapy approach originated by Carl Rogers. The goals of therapy are to promote the client’s congruence, self awareness, and self acceptance. This approach views the client as naturally directed toward self actualization, and only needing facilitative conditions in order to promote this tendency.
A family of cellular proteins that mediate the correct assembly or disassembly of polypeptides and their associated ligands. Although they take part in the assembly process, molecular chaperones are not components of the final structures.
Membrane limited structures derived from cell membranes and cytoplasmic material, and released into EXTRACELLULAR SPACE. They circulate through the EXTRACELLULAR FLUID and through the peripheral blood in the MICROVASCULATURE where cells, much larger, cannot, thereby affecting a variety of intercellular communication processes.
Within medicine, nutrition (the study of food and the effect of its components on the body) has many different roles. Appropriate nutrition can help prevent certain diseases, or treat others. In critically ill patients, artificial feeding by tubes need t...
Stress is caused by your perception of situations around you and then the reaction of your body to them. The automatic stress response to unexpected events is known as 'fight or flight'. Discovered by Walter Cannon in 1932, it is the release of h...