Title
AIMP2-DX2 provides therapeutic interface to control KRAS-driven tumorigenesis
Author
Dae Gyu Kim, Yongseok Choi, Yuno Lee, Semi Lim, Jiwon Kong, JaeHa Song, Younah Roh, Dipesh S. Harmalkar, Kwanshik Lee, Ja-il Goo, Hye Young Cho, Ameeq Ul Mushtaq, Jihye Lee, Song Hwa Park, Doyeun Kim, Byung Soh Min, Kang Young Lee, Young Ho Jeon, Sunkyung Lee, Kyeong Lee & Sunghoon Kim
Year
2022
Journal
Nature Communications
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.
Full Article
Instrument
FP-6500
Keywords
KRAS, AIMP-DX2,G-domain