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  • Title: Geldanamycin inhibits tyrosine phosphorylation-dependent NF-kappaB activation.
    Author: Crèvecoeur J, Merville MP, Piette J, Gloire G.
    Journal: Biochem Pharmacol; 2008 Jun 01; 75(11):2183-91. PubMed ID: 18455150.
    Abstract:
    Hsp90 is a protein chaperone regulating the stability and activity of many signalling molecules. The requirement of Hsp90 activity in the NF-kappaB pathway has been recently reported by several authors using the Hsp90 ATPase inhibitor geldanamycin (GA), an anti-tumor drug. Hsp90 inhibition blocks the synthesis and activation of the IKK complex, the major kinases complex responsible for IkappaBalpha phosphorylation on serine 32 and 36, a key step for its degradation and the nuclear translocation of NF-kappaB. However, the effect of GA on other IkappaBalpha kinases, including tyrosine kinases, is unknown. In the present study, we investigated the effect of GA on NF-kappaB activation induced by sodium pervanadate (PV), a tyrosine phosphatase inhibitor triggering c-Src-mediated tyrosine phosphorylation of IkappaBalpha. We report for the first time that GA inhibits PV-induced IkappaBalpha tyrosine phosphorylation and degradation. Using an in vitro kinase assay, we demonstrated that GA inhibits the activity of c-Src as an IkappaBalpha tyrosine kinase, but not its cellular expression. As a result, GA blocked PV-induced NF-kappaB DNA-binding activity on an exogenous kappaB element and on the endogenous ikappabalpha promoter, thereby inhibiting ikappabalpha transcription. Finally, we demonstrated that, despite NF-kappaB inhibition, pre-treatment with GA does not potentiate PV-induced apoptosis. We conclude that c-Src requires Hsp90 for its tyrosine kinase activity, and its inhibition by GA blocks c-Src-dependent signalling pathways, such as NF-kappaB activation induced by sodium pervanadate. The effect of GA on PV-induced apoptosis is discussed in the light of recent publications in the literature.
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