The regulatory mechanism of Hsp90alpha secretion and its function in tumor malignancy.
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.
Wang
Xiaofeng
X
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.
Song
Xiaomin
X
Zhuo
Wei
W
Fu
Yan
Y
Shi
Hubing
H
Liang
Yun
Y
Tong
Maomeng
M
Chang
Guodong
G
Luo
Yongzhang
Y
D020816:Amino Acid Motifs; D001665:Binding Sites; D014408:Biomarkers, Tumor / Q000032:analysis; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D009362:Neoplasm Metastasis / Q000473:pathology*; D009369:Neoplasms / Q000473:pathology*; D009687:Nuclear Proteins / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation; D012720:Severity of Illness Index
D014408:Biomarkers, Tumor; D018841:HSP90 Heat-Shock Proteins; C533585:HSP90AA2P protein, human; D009687:Nuclear Proteins; D017868:Cyclic AMP-Dependent Protein Kinases; D010749:Phosphoprotein Phosphatases; C089641:protein phosphatase 5