Research Center, Shriners Hospital for Children, Department of Cell & Developmental Biology, Oregon Health & Science University, Portland, Oregon 97239, USA.
J Biol Chem. 2011 Jun 3;286(22):19597-604. doi: 10.1074/jbc.M110.206151. Epub 2011 Apr 12.
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.
成纤维细胞生长因子受体 3（FGFR3）是生长和分化的关键调节剂，其异常激活导致包括软骨发育不全和癌症在内的多种遗传疾病。热休克蛋白 90（Hsp90）是一种专门的分子伴侣，参与稳定一组称为客户的特定蛋白质。在这里，我们描述了 Hsp90 和共伴侣 Cdc37 与 FGFR3 和 FGFR 家族的关系。FGFR3 与这些伴侣复合物强烈相关，并依赖于它们的稳定性和功能。使用 geldanamycin 类似物 17-AAG 抑制 Hsp90 功能会诱导 FGFR3 的泛素化和降解，并降低 FGFR3 的信号转导能力。其他 FGFR 与这些伴侣的相互作用较弱，并且受到 Hsp90 抑制的差异影响。Hsp90 相关的泛素连接酶 CHIP 能够相互作用并使 FGFR3 不稳定。我们的结果确立了 FGFR3 作为 Hsp90 的强客户，并表明调节 Hsp90 伴侣复合物可能有益于影响疾病中 FGFR3 的稳定性和功能。
