Heat Shock Protein 90 Chaperone Regulates the E3 Ubiquitin-Ligase Hakai Protein Stability
Heat Shock Protein 90 Chaperone Regulates the E3 Ubiquitin-Ligase Hakai Protein Stability
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DOI：
10.3390/cancers12010215
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发表时间：
2020-01-01
期刊：
影响因子：
5.2
通讯作者：
Figueroa, Angelica
中科院分区：
文献类型：
--
作者：
Diaz-Diaz, Andrea;Roca-Lema, Daniel;Figueroa, Angelica
E3泛素连接酶Hakai与几种酪氨酸磷酸化的Src底物结合，包括上皮-间充质转化E-钙粘蛋白的标志，并发出降解其特异性靶标的信号。Hakai在包括结肠癌在内的多种人类癌症中高度表达，被认为是癌症治疗的药物靶标。在这里，我们报告的哈凯和热休克蛋白90（Hsp 90）伴侣复合物之间的联系。Hsp 90参与其客户蛋白的正确折叠，使其保持稳定性和活性。Hsp 90抑制剂特异性干扰与其Hsp 90客户蛋白的关联，并表现出有效的抗癌特性。通过免疫沉淀，我们提出的证据表明，Hakai相互作用与Hsp 90伴侣复合物在几个上皮细胞，并证明这是一个新的Hsp 90客户端蛋白。有趣的是，通过Hakai的过表达和敲低实验，我们将Annexin A2鉴定为Hakai调节的蛋白。格尔德霉素对Hsp 90的药理学抑制导致Hakai以溶酶体依赖性方式降解。有趣的是，格尔德霉素诱导的Hakai降解伴随着E-钙粘蛋白和膜联蛋白A2的表达增加。我们还表明，格尔德霉素抑制细胞运动至少部分通过其对哈凯表达的作用。总之，我们的研究结果确定Hakai作为一种新的Hsp 90客户端蛋白，并阐明了Hakai稳定性的调节。我们的研究结果打开了可能性的Hsp 90抑制剂的结肠直肠癌治疗的潜在用途，通过其对Hsp 90的Hakai客户蛋白的作用。
The E3 ubiquitin-ligase Hakai binds to several tyrosine-phosphorylated Src substrates, including the hallmark of the epithelial-to-mesenchymal transition E-cadherin, and signals for degradation of its specific targets. Hakai is highly expressed in several human cancers, including colon cancer, and is considered as a drug target for cancer therapy. Here, we report a link between Hakai and the heat shock protein 90 (Hsp90) chaperone complex. Hsp90 participates in the correct folding of its client proteins, allowing them to maintain their stability and activity. Hsp90 inhibitors specifically interfere with the association with its Hsp90 client proteins, and exhibit potent anti-cancer properties. By immunoprecipitation, we present evidence that Hakai interacts with Hsp90 chaperone complex in several epithelial cells and demonstrate that is a novel Hsp90 client protein. Interestingly, by overexpressing and knocking-down experiments with Hakai, we identified Annexin A2 as a Hakai-regulated protein. Pharmacological inhibition of Hsp90 with geldanamycin results in the degradation of Hakai in a lysosome-dependent manner. Interestingly, geldanamycin-induced Hakai degradation is accompanied by an increased expression of E-cadherin and Annexin A2. We also show that geldanamycin suppresses cell motility at least in part through its action on Hakai expression. Taken together, our results identify Hakai as a novel Hsp90 client protein and shed light on the regulation of Hakai stability. Our results open the possibility to the potential use of Hsp90 inhibitors for colorectal cancer therapy through its action on Hakai client protein of Hsp90.