Critical regulation of TGFβ signaling by Hsp90

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Abstract
Transforming growth factor β (TGFβ) controls a diverse set of cellular processes by activating TGFβ type I (TβRI) and type II (TβRII) serine-threonine receptor kinases. Canonical TGFβ signaling is mediated by Smad2 and Smad3, which are phosphorylated in their SXS motif by activated TβRI. The 90-kDa heat-shock protein (Hsp90) is a molecular chaperone facilitating the folding and stabilization of many protein kinases and intracellular signaling molecules. Here, we present evidence identifying a critical role for Hsp90 in TGFβ signaling. Inhibition of Hsp90 function by using small-molecule inhibitors such as 17-allylamino-17-demethoxygeldanamycin (17AAG), and also at the genetic level, blocks TGFβ-induced signaling and transcriptional responses. Furthermore, we identify TβRI and TβRII as Hsp90-interacting proteins in vitro and in vivo and demonstrate that inhibition of Hsp90 function increases TβR ubiquitination and degradation dependent on the Smurf2 ubiquitin E3 ligase. Our data reveal an essential level of TGFβ signaling regulation mediated by Hsp90 by its ability to chaperone TβRs and also implicate the use of Hsp90 inhibitors in blocking undesired activation of TGFβ signaling in diseases.