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Chaperone-dependent E3 ubiquitin ligase CHIP mediates a degradative pathway for c-ErbB2/Neu
It is shown that the chaperone-binding ubiquitin ligase CHIP efficiently ubiquitinates and down-regulates ErbB2, and a previously unrecognized pathway, amenable to pharmacologic manipulation, that mediates Erb B2 stability is described.
CHIP activates HSF1 and confers protection against apoptosis and cellular stress
It is demonstrated that the dual function co‐chaperone/ubiquitin ligase CHIP (C‐terminus of Hsp70‐interacting protein) regulates activation of the stress‐ chaperone response through induced trimerization and transcriptional activation of HSF1, and is required for protection against stress‐induced apoptosis in murine fibroblasts.
Molecular chaperone TRAP1 regulates a metabolic switch between mitochondrial respiration and aerobic glycolysis
Significance TNF receptor-associated protein (TRAP1) is found predominantly in mitochondria. A possible direct impact of TRAP1 on mitochondrial metabolism remains unexplored. We used TRAP1-null cells
Sensitivity of Mature ErbB2 to Geldanamycin Is Conferred by Its Kinase Domain and Is Mediated by the Chaperone Protein Hsp90*
The data suggest that Hsp90 uniquely stabilizes ErbB2 via interaction with its kinase domain and that GA stimulates Erb B2 degradation secondary to disruption of Er bBB2/Hsp90 association.
Drug‐induced ubiquitylation and degradation of ErbB receptor tyrosine kinases: implications for cancer therapy
An unexpected activity of TKIs is reported: along with inhibition of tyrosine phosphorylation, they enhance ubiquitylation and accelerate endocytosis and subsequent intracellular destruction of ErbB‐2 molecules.
Surface charge and hydrophobicity determine ErbB2 binding to the Hsp90 chaperone complex
A loop within the N lobe of the kinase domain of ErbB2 that determines Hsp90 binding is identified, and the amino acid sequence of the loop determines the electrostatic and hydrophobic character of the protein's surface, which in turn govern interaction with HSp90.
Regulation of Hsp90 client proteins by a Cullin5-RING E3 ubiquitin ligase
A link between Cullin5 (Cul5) E3 ubiquitin ligase and the heat shock protein 90 (Hsp90) chaperone complex is reported, which has implications in the effectiveness of Hsp90 targeted chemotherapy, which is currently undergoing clinical trials.
Hsp90 inhibition transiently activates Src kinase and promotes Src-dependent Akt and Erk activation.
The prototypical Hsp90 inhibitor geldanamycin induces Akt and Erk activation that is independent of PTEN status and is mediated by transient activation of Src kinase, suggesting that Src activation results directly from dissociation of the chaperone.