Critical regulation of TGFβ signaling by Hsp90

Abstract

Transforming growth factor ␤ (TGF␤) controls a diverse set of cellular processes by activating TGF␤ type I (T␤RI) and type II (T␤RII) serine-threonine receptor kinases. Canonical TGF␤ signaling is mediated by Smad2 and Smad3, which are phosphorylated in their SXS motif by activated T␤RI. 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 TGF␤ signaling. Inhibition of Hsp90 function by using small-molecule inhibitors such as 17-allylamino-17-demethoxygeldanamycin (17AAG), and also at the genetic level, blocks TGF␤-induced signaling and transcriptional responses. Furthermore, we identify T␤RI and T␤RII as Hsp90-interacting proteins in vitro and in vivo and demonstrate that inhibition of Hsp90 function increases T␤R ubiquitination and degradation dependent on the Smurf2 ubiquitin E3 ligase. Our data reveal an essential level of TGF␤ signaling regulation mediated by Hsp90 by its ability to chaperone T␤Rs and also implicate the use of Hsp90 inhibitors in blocking undesired activation of TGF␤ signaling in diseases.Smad ͉ Smurf ͉ tumor suppression ͉ degra T GF␤ signals through heteromeric complexes of transmembrane serine-threonine kinase receptors to control diverse developmental processes and the pathogenesis of many diseases. Within the receptor complex, the TGF␤ type II receptor (T␤RII) is constitutively active and phosphorylates the TGF␤ type I receptor (T␤RI) on serine-threonine residues in the GS domain in response to TGF␤. Activated T␤RI then phosphorylates Smad2 and Smad3

Heat shock protein 90 inhibitor attenuates renal fibrosis through degradation of transforming growth factor-β type II receptor

“…12,14 Interestingly, a recent study has identified TbRI and TbRII as Hsp90 client proteins. 15 However, the clinical significance of Hsp90 inhibitors in disease models with aberrant TGF-b responses remains to be determined. Here, we examined whether Hsp90 might regulate TGF-b1 signaling in renal cells and determined the effect of Hsp90 inhibitors in cultured renal cells and in a model of renal fibrosis.…”

Regulating the stability of TGFβ receptors and Smads

“…In this complex, the N-terminal part of Smad7 facilitates Smurf2 activity by helping recruit the E2 conjugating enzyme UbcH7 [29]. Recently, it was shown that the heat shock protein 90 (Hsp90) is a modifier of Smurf2-mediated receptor ubiquitination, as inhibiting Hsp90 activity led to an increased receptor ubiquitination [30]. This effect is due to the ability of Hsp90 to bind and chaperone the receptors.…”

Signaling Receptors for TGF-β Family Members

“…The chaperone protein, Hsp90, binds to TbRII and TbRI and protects them from association with the ubiquitin ligase Smurf2, thus stabilizing active receptor complexes and promoting Smad signaling downstream of TGF-b (Wrighton et al 2008). The adaptor protein TLP (TRAP-1-like protein) associates with TbRII (and activin receptors) and with Smad4 (Felici et al 2003).…”