Heat shock protein 90–Signal transducer and activator of transcription 3 interface (Hsp90–STAT3 interface) (Hsp90–STAT3 interface)

The Heat shock protein 90–Signal transducer and activator of transcription 3 (Hsp90–STAT3) interface represents a specialized protein-protein interaction (PPI) where the Hsp90 molecular chaperone maintains the conformational stability and functional integrity of the STAT3 transcription factor (Prinsloo et al., 2012). STAT3 is a central coordinator of various oncogenic signaling pathways, including those initiated by IL-6 and JAK family kinases, and its constitutive activation is a hallmark of many solid and hematological tumors (Bhatia et al., 2018). By binding to STAT3, Hsp90 protects it from ubiquitin-mediated proteasomal degradation and facilitates its phosphorylation and subsequent nuclear translocation. Therapeutic intervention targeting this interface, primarily through Hsp90 inhibitors like Tanespimycin or Ganetespib, results in the rapid depletion of STAT3 protein levels and the suppression of genes involved in cell cycle progression and anti-apoptosis (Schoof et al., 2009). This strategy is particularly attractive for treating cancers that have developed resistance to direct kinase inhibitors. However, the clinical utility of targeting this interface is currently limited by the broad-spectrum effects of Hsp90 inhibition, which can lead to toxicities such as hepatotoxicity and visual disturbances, as well as the induction of a compensatory heat shock response (Whitesell & Lindquist, 2005).

Other names

Hsp90-STAT3 complexHsp90/STAT3 interactionHsp90-STAT3 PPI

Disruption of the Hsp90–STAT3 interaction prevents the chaperone-mediated stabilization of STAT3, leading to its proteasomal degradation and the inhibition of STAT3-mediated gene transcription.