Geldanamycin selectively targets the nascent form of ERBB3 for degradation
Geldanamycin selectively targets the nascent form of ERBB3 for degradation
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DOI：
10.1007/s12192-009-0166-1
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发表时间：
2010-09-01
影响因子：
3.8
通讯作者：
Landgraf, Ralf
中科院分区：
文献类型：
--
作者：
Gerbin, Candice S.;Landgraf, Ralf
热休克蛋白90(HSP90)针对广泛的客户蛋白，具有不同的相互作用模式和后果。同源的表皮生长因子受体(EGFR)和ERBB2受体及其激酶缺陷型突变体在受体的初生期和成熟期对HSP90的需求不同。HSP90与成熟的ERBB2的选择性结合可能与该激活域的特性有关。我们评估了HSP90对同源ERBB3受体的作用。ErbB3天然缺乏激酶，是细胞存活和应激反应的中心介质，也是ERBB2在信号转导中的主要二聚化伙伴。细胞研究表明，与EGFR类似，ERBB3和HSP90结合的格尔达那霉素(GA)敏感性处于萌芽状态，并依赖于ERBB3激动域的存在。此外，尽管ERBB3天生缺乏激酶活性，而且与报道的成熟和缺乏激酶的EGFR对GA的敏感性相反，新生状态的ERBB3对GA的敏感性似乎是排他的。格尔达那霉素在ERBB3和HSP90的相互作用中被破坏，并在ERBB3从内质网输出之前的早期合成阶段抑制ERBB3的成熟。对ERBB3的光可转换融合蛋白的研究表明，在成熟的后期阶段，格尔达那霉素敏感，可能是通过HSP90在结构校对中的假定作用。
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.