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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  ;  Sunghoon Kim 
 NATURE COMMUNICATIONS, Vol.13(1) : 2572, 2022-05 
Journal Title
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Cell Transformation, Neoplastic ; Humans ; Lung Neoplasms* / drug therapy ; Lung Neoplasms* / genetics ; Lung Neoplasms* / metabolism ; Nuclear Proteins / metabolism ; Proto-Oncogene Proteins p21(ras)* / genetics ; Proto-Oncogene Proteins p21(ras)* / metabolism ; Ubiquitin / metabolism ; Ubiquitin-Protein Ligases / metabolism
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.
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1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
Min, Byung Soh(민병소) ORCID logo https://orcid.org/0000-0003-0180-8565
Lee, Kang Young(이강영)
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