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- Title
AIMP2-DX2 provides therapeutic interface to control KRAS-driven tumorigenesis.
- Authors
Kim, Dae Gyu; Choi, Yongseok; Lee, Yuno; Lim, Semi; Kong, Jiwon; Song, JaeHa; Roh, Younah; Harmalkar, Dipesh S.; Lee, Kwanshik; Goo, Ja-il; Cho, Hye Young; Mushtaq, Ameeq Ul; Lee, Jihye; Park, Song Hwa; Kim, Doyeun; Min, Byung Soh; Lee, Kang Young; Jeon, Young Ho; Lee, Sunkyung; Lee, Kyeong
- Abstract
Recent development of the chemical inhibitors specific to oncogenic KRAS (Kirsten Rat Sarcoma 2 Viral Oncogene Homolog) mutants revives much interest to control KRAS-driven cancers. Here, we report that AIMP2-DX2, a variant of the tumor suppressor AIMP2 (aminoacyl-tRNA synthetase-interacting multi-functional protein 2), acts as a cancer-specific regulator of KRAS stability, augmenting KRAS-driven tumorigenesis. AIMP2-DX2 specifically binds to the hypervariable region and G-domain of KRAS in the cytosol prior to farnesylation. Then, AIMP2-DX2 competitively blocks the access of Smurf2 (SMAD Ubiquitination Regulatory Factor 2) to KRAS, thus preventing ubiquitin-mediated degradation. Moreover, AIMP2-DX2 levels are positively correlated with KRAS levels in colon and lung cancer cell lines and tissues. We also identified a small molecule that specifically bound to the KRAS-binding region of AIMP2-DX2 and inhibited the interaction between these two factors. Treatment with this compound reduces the cellular levels of KRAS, leading to the suppression of KRAS-dependent cancer cell growth in vitro and in vivo. These results suggest the interface of AIMP2-DX2 and KRAS as a route to control KRAS-driven cancers. Direct targeting of oncogenic KRAS activity is a challenge. Here the authors report that a splice variant of AIMP2, AIMP2-DX2, enhances KRAS stability by blocking ubiquitin-mediated degradation of KRAS via the E3 ligase, Smurf2, and identify a chemical that can hinder AIMP2-DX2 from interacting with KRAS.
- Subjects
CANCER cell growth; UBIQUITIN ligases; SMALL molecules; UBIQUITINATION; RAS oncogenes; HYPERVARIABLE regions; CANCER cells; TUMOR suppressor proteins
- Publication
Nature Communications, 2022, Vol 13, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-022-30149-2