title: Fibroblast growth factor receptor 3 (FGFR3) is a strong heat shock protein 90 (Hsp90) client: implications for therapeutic manipulation.
abstract: Fibroblast growth factor receptor 3 (FGFR3) is a key regulator of growth and differentiation, whose aberrant activation causes a number of genetic diseases including achondroplasia and cancer. Hsp90 is a specialized molecular chaperone involved in stabilizing a select set of proteins termed clients. Here, we delineate the relationship of Hsp90 and co-chaperone Cdc37 with FGFR3 and the FGFR family. FGFR3 strongly associates with these chaperone complexes and depends on them for stability and function. Inhibition of Hsp90 function using the geldanamycin analog 17-AAG induces the ubiquitination and degradation of FGFR3 and reduces the signaling capacity of FGFR3. Other FGFRs weakly interact with these chaperones and are differentially influenced by Hsp90 inhibition. The Hsp90-related ubiquitin ligase CHIP is able to interact and destabilize FGFR3. Our results establish FGFR3 as a strong Hsp90 client and suggest that modulating Hsp90 chaperone complexes may beneficially influence the stability and function of FGFR3 in disease.
authors.affiliation: Research Center, Shriners Hospital for Children, Department of Cell & Developmental Biology, Oregon Health & Science University, Portland, Oregon 97239, USA.
authors.forename: Melanie B
authors.initials: MB
authors.lastname: Laederich
authors.forename: Catherine R
authors.initials: CR
authors.lastname: Degnin
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Lunstrum
authors.forename: Paul
authors.initials: P
authors.lastname: Holden
authors.forename: William A
authors.initials: WA
authors.lastname: Horton
mesh_terms: D000130:Achondroplasia / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology; D019556:COS Cells; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D018833:Chaperonins / Q000235:genetics / Q000378:metabolism; D002522:Chlorocebus aethiops; D004795:Enzyme Stability / Q000187:drug effects / Q000235:genetics; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D051379:Mice; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D016227:Benzoquinones; C498362:CDC37 protein, human; C513271:Cdc37 protein, mouse; D018797:Cell Cycle Proteins; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D018832:Molecular Chaperones; C112765:tanespimycin; C496365:FGFR3 protein, human; C496366:Fgfr3 protein, mouse; D051498:Receptor, Fibroblast Growth Factor, Type 3; D018833:Chaperonins