成纤维细胞生长因子受体 3（FGFR3）是一种强烈的热休克蛋白 90（Hsp90）客户：对治疗干预的影响。
Fibroblast growth factor receptor 3 (FGFR3) is a strong heat shock protein 90 (Hsp90) client: implications for therapeutic manipulation.
机构信息
Research Center, Shriners Hospital for Children, Department of Cell & Developmental Biology, Oregon Health & Science University, Portland, Oregon 97239, USA.
出版信息
J Biol Chem. 2011 Jun 3;286(22):19597-604. doi: 10.1074/jbc.M110.206151. Epub 2011 Apr 12.
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.
摘要
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。
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本文引用的文献
1
Achondroplasia: pathogenesis and implications for future treatment.软骨发育不全症：发病机制及对未来治疗的影响。
Curr Opin Pediatr. 2010 Aug;22(4):516-23. doi: 10.1097/MOP.0b013e32833b7a69.
2
Peripheral protein quality control removes unfolded CFTR from the plasma membrane.外周蛋白质量控制系统将未折叠的 CFTR 从质膜中移除。
Science. 2010 Aug 13;329(5993):805-10. doi: 10.1126/science.1191542. Epub 2010 Jul 1.
3
HSP90 at the hub of protein homeostasis: emerging mechanistic insights.HSP90 作为蛋白质平衡的枢纽：新兴的机制见解。
Nat Rev Mol Cell Biol. 2010 Jul;11(7):515-28. doi: 10.1038/nrm2918. Epub 2010 Jun 9.
4
New molecular and biological mechanism of antitumor activities of KW-2478, a novel nonansamycin heat shock protein 90 inhibitor, in multiple myeloma cells.新型非安莎霉素热休克蛋白 90 抑制剂 KW-2478 抑制多发性骨髓瘤细胞的抗肿瘤作用的新分子和生物学机制。
Clin Cancer Res. 2010 May 15;16(10):2792-802. doi: 10.1158/1078-0432.CCR-09-3112. Epub 2010 Apr 20.
5
Hsp90 inhibitors block outgrowth of EBV-infected malignant cells in vitro and in vivo through an EBNA1-dependent mechanism.Hsp90 抑制剂通过一种依赖于 EBNA1 的机制在体外和体内阻断 EBV 感染的恶性细胞的生长。
Proc Natl Acad Sci U S A. 2010 Feb 16;107(7):3146-51. doi: 10.1073/pnas.0910717107. Epub 2010 Jan 26.
6
Asymmetric receptor contact is required for tyrosine autophosphorylation of fibroblast growth factor receptor in living cells.在活细胞中，成纤维细胞生长因子受体的酪氨酸自身磷酸化需要不对称的受体接触。
Proc Natl Acad Sci U S A. 2010 Feb 16;107(7):2866-71. doi: 10.1073/pnas.0914157107. Epub 2010 Jan 26.
7
De-regulated FGF receptors as therapeutic targets in cancer.异常激活的 FGF 受体作为癌症治疗靶点。
Pharmacol Ther. 2010 Jan;125(1):105-17. doi: 10.1016/j.pharmthera.2009.10.001. Epub 2009 Oct 27.
8
Update on Hsp90 inhibitors in clinical trial.临床试验中 HSP90 抑制剂的最新进展
Curr Top Med Chem. 2009;9(15):1479-92. doi: 10.2174/156802609789895728.
9
Characterization of celastrol to inhibit hsp90 and cdc37 interaction.鉴定雷公藤红素抑制 HSP90 和 Cdc37 相互作用。
J Biol Chem. 2009 Dec 18;284(51):35381-9. doi: 10.1074/jbc.M109.051532.
10
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