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

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 () and Sunghoon Kim ()
Additional contact information
Dae Gyu Kim: Yonsei University
Yongseok Choi: Korea University
Yuno Lee: Korea Research Institute of Chemical Technology
Semi Lim: Yonsei University
Jiwon Kong: Yonsei University
JaeHa Song: Yonsei University
Younah Roh: Yonsei University
Dipesh S. Harmalkar: Korea University
Kwanshik Lee: Korea University
Ja-il Goo: Korea University
Hye Young Cho: Korea University
Ameeq Ul Mushtaq: Korea University
Jihye Lee: Yonsei University
Song Hwa Park: Yonsei University
Doyeun Kim: Yonsei University
Byung Soh Min: Yonsei University
Kang Young Lee: Yonsei University
Young Ho Jeon: Korea University
Sunkyung Lee: Korea Research Institute of Chemical Technology
Kyeong Lee: Dongguk University
Sunghoon Kim: Yonsei University

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: 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.

Date: 2022
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-022-30149-2 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30149-2

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-022-30149-2

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().