Department of Biological Chemistry, University of California Los Angeles, Los Angeles, CA, USA.
Cell Stress Chaperones. 2010 Sep;15(5):529-44. doi: 10.1007/s12192-009-0166-1. Epub 2010 Jan 19.
Heat shock protein 90 (HSP90) targets a broad spectrum of client proteins with divergent modes of interaction and consequences. The homologous epidermal growth factor receptor (EGFR) and ERBB2 receptors as well as kinase-deficient mutants thereof differ in their requirement for HSP90 in the nascent versus mature state of the receptor. Specific features of the kinase domain have been implicated for the selective association of HSP90 with mature ERBB2. We evaluated the role of HSP90 for the homologous ERBB3 receptor. ERBB3 is naturally kinase deficient, a central mediator in cell survival and stress response and the primary dimerization partner for ERBB2 in signaling. Cellular studies indicate that, similar to EGFR, the geldanamycin (GA) sensitivity of ERBB3 and HSP90 binding resides in the nascent state and is dependent on the presence of the kinase domain of ERBB3. Furthermore, despite its intrinsic lack of kinase activity and in contrast to the reported GA sensitivity of mature and kinase-deficient EGFR, the GA sensitivity of the nascent state of ERBB3 appears to be exclusive. Geldanamycin disrupts the interaction of ERBB3 and HSP90 and inhibits ERBB3 maturation at an early stage of synthesis, prior to export from the ER. Studies with a photo-convertible fusion protein of ERBB3 suggest geldanamycin sensitivity at a later stage in maturation, possibly through the putative role of HSP90 in structural proofreading.
热休克蛋白 90（HSP90）以不同的相互作用模式和结果靶向广泛的客户蛋白。同源表皮生长因子受体（EGFR）和 ERBB2 受体及其激酶缺陷突变体在受体的初始状态和成熟状态下对 HSP90 的需求不同。激酶结构域的特定特征被认为是 HSP90 与成熟 ERBB2 选择性结合的原因。我们评估了 HSP90 对同源 ERBB3 受体的作用。ERBB3 天然缺乏激酶活性，是细胞存活和应激反应的中心介质，也是 ERBB2 信号转导中的主要二聚化伴侣。细胞研究表明，与 EGFR 相似，GA 对 ERBB3 和 HSP90 结合的敏感性存在于初始状态，并且依赖于 ERBB3 激酶结构域的存在。此外，尽管 ERBB3 具有内在的缺乏激酶活性，并且与报道的成熟和激酶缺陷型 EGFR 的 GA 敏感性相反，ERBB3 的新生状态的 GA 敏感性似乎是排他性的。GA 破坏 ERBB3 和 HSP90 的相互作用，并在 ER 内从内质网输出之前，在合成的早期阶段抑制 ERBB3 的成熟。使用 ERBB3 的光转化融合蛋白的研究表明，在成熟的后期阶段存在 GA 敏感性，可能是通过 HSP90 在结构校对中的假定作用。
