AIMP2-DX2 provides therapeutic interface to control KRAS-driven tumorigenesis

Dae Gyu Kim, Yongseok Choi, Yuno Lee, Semi Lim, Jiwon Kong, Jae Ha 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 LeeSunghoon Kim

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

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.

Original languageEnglish
Article number2572
JournalNature communications
Volume13
Issue number1
DOIs
Publication statusPublished - 2022 Dec

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • General
  • Physics and Astronomy(all)

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