Targeting the interaction of AIMP2-DX2 with HSP70 suppresses cancer development.

A tumorigenic factor, AIMP2 lacking exon 2 (AIMP2-DX2), is often upregulated in many cancers. However, how its cellular level is determined is not understood. Here, we report heat-shock protein HSP70 as a critical determinant for the level of AIMP2-DX2. Interaction of the two factors was identified by interactome analysis and ...
structurally determined by X-ray crystallography and NMR analyses. HSP70 recognizes the amino (N)-terminal flexible region, as well as the glutathione S-transferase domain of AIMP2-DX2, via its substrate-binding domain, thus blocking the Siah1-dependent ubiquitination of AIMP2-DX2. AIMP2-DX2-induced cell transformation and cancer progression in vivo was further augmented by HSP70. A positive correlation between HSP70 and AIMP2-DX2 levels was shown in various lung cancer cell lines and patient tissues. Chemical intervention in the AIMP2-DX2-HSP70 interaction suppressed cancer cell growth in vitro and in vivo. Thus, this work demonstrates the importance of the interaction between AIMP2-DX2 and HSP70 on tumor progression and its therapeutic potential against cancer.
Mesh Terms:
Alternative Splicing, Animals, Cell Line, Tumor, Cell Transformation, Neoplastic, Crystallography, X-Ray, Disease Progression, Female, Gene Expression Regulation, Neoplastic, HEK293 Cells, HSP70 Heat-Shock Proteins, Humans, Lung Neoplasms, Magnetic Resonance Spectroscopy, Mice, Mice, Inbred BALB C, Nuclear Proteins, Protein Binding, Protein Interaction Mapping, Protein Multimerization, Surface Plasmon Resonance, Ubiquitin
Nat. Chem. Biol.
Date: Dec. 01, 2019
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