热休克蛋白 90α 的分泌调控机制及其在肿瘤恶性行为中的功能。
The regulatory mechanism of Hsp90alpha secretion and its function in tumor malignancy.
机构信息
National Engineering Laboratory for Anti-tumor Protein Therapeutics, Beijing Key Laboratory for Protein Therapeutics, Cancer Biology Laboratory, Department of Biological Sciences and Biotechnology, Tsinghua University, Beijing 100084, China.
出版信息
Proc Natl Acad Sci U S A. 2009 Dec 15;106(50):21288-93. doi: 10.1073/pnas.0908151106. Epub 2009 Nov 24.
Heat shock protein 90-alpha (Hsp90alpha) is an intracellular molecular chaperone. However, it can also be secreted with the underlying regulatory mechanism remaining far from clear. Here we show that the secreted Hsp90alpha is a C-terminal truncated form and its secretion is regulated by the C-terminal EEVD motif via interacting with proteins containing tetratricopeptide repeat domains. We also demonstrate that secretion of Hsp90alpha is determined by the phosphorylation status at residue Thr-90, regulated by protein kinase A and protein phosphatase 5. We further demonstrate that the secretion of Hsp90alpha is a prerequisite for its proinvasiveness function and blocking the secreted Hsp90alpha results in significant inhibition of tumor metastasis. Meanwhile, the level of plasma Hsp90alpha is positively correlated with tumor malignancy in clinical cancer patients. In sum, our results reveal the regulatory mechanism of Hsp90alpha secretion, and its function in tumor invasiveness, indicating it can be a promising diagnostic marker for tumor malignancy in clinical application.
热休克蛋白 90-α（Hsp90α）是一种细胞内分子伴侣。然而，它也可以被分泌，其潜在的调节机制仍不清楚。在这里，我们表明分泌的 Hsp90α是 C 端截断形式，其分泌受 C 端 EEVD 基序调节，通过与含有四肽重复结构域的蛋白质相互作用。我们还证明，Hsp90α 的分泌取决于残基 Thr-90 的磷酸化状态，受蛋白激酶 A 和蛋白磷酸酶 5 调节。我们进一步证明 Hsp90α 的分泌是其侵袭功能所必需的，阻断分泌的 Hsp90α 可显著抑制肿瘤转移。同时，血浆 Hsp90α 的水平与临床癌症患者的肿瘤恶性程度呈正相关。总之，我们的研究结果揭示了 Hsp90α 分泌的调节机制及其在肿瘤侵袭性中的功能，表明它可能成为临床应用中肿瘤恶性程度的有前途的诊断标志物。
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