Critical regulation of TGFbeta signaling by Hsp90.
Transforming growth factor beta (TGFbeta) controls a diverse set of cellular processes by activating TGFbeta type I (TbetaRI) and type II (TbetaRII) serine-threonine receptor kinases. Canonical TGFbeta signaling is mediated by Smad2 and Smad3, which are phosphorylated in their SXS motif by activated TbetaRI. 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 TGFbeta signaling. Inhibition of Hsp90 function by using small-molecule inhibitors such as 17-allylamino-17-demethoxygeldanamycin (17AAG), and also at the genetic level, blocks TGFbeta-induced signaling and transcriptional responses. Furthermore, we identify TbetaRI and TbetaRII as Hsp90-interacting proteins in vitro and in vivo and demonstrate that inhibition of Hsp90 function increases TbetaR ubiquitination and degradation dependent on the Smurf2 ubiquitin E3 ligase. Our data reveal an essential level of TGFbeta signaling regulation mediated by Hsp90 by its ability to chaperone TbetaRs and also implicate the use of Hsp90 inhibitors in blocking undesired activation of TGFbeta signaling in diseases.
Wrighton
Katharine H
KH
Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA.
Lin
Xia
X
Feng
Xin-Hua
XH
D020816:Amino Acid Motifs; D016227:Benzoquinones / Q000494:pharmacology; D002460:Cell Line; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051899:Smad2 Protein / Q000737:chemistry / Q000378:metabolism; D051900:Smad3 Protein / Q000737:chemistry / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; C112765:tanespimycin; C471641:SMURF2 protein, human; D044767:Ubiquitin-Protein Ligases