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.
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Chemical induction of the interaction between AIMP2-DX2 and Siah1 to enhance ubiquitination.
Cell Chem Biol
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College of Pharmacy, Dongguk University, Goyang 10326, Republic of Korea. Electronic address:
Article Synopsis
- AIMP2-DX2 (DX2) is a variant of a protein linked to cancer, and reducing its levels can help stop tumor growth.
- Researchers found that a compound called SDL01 enhances the interaction between DX2 and another protein, Siah1, promoting DX2's degradation.
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