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 Lee; Sunghoon Kim

doi:10.1038/s41467-022-30149-2

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 Lee

Sunghoon Kim

Department of Pharmacy

Research output: Contribution to journal › Article › peer-review

10 Scopus citations

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 language	English
Article number	2572
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-30149-2
State	Published - Dec 2022

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Kim, D. G., Choi, Y., Lee, Y., Lim, S., Kong, J., Song, J. H., Roh, Y., Harmalkar, D. S., Lee, K., Goo, J. I., Cho, H. Y., Mushtaq, A. U., Lee, J., Park, S. H., Kim, D., Min, B. S., Lee, K. Y., Jeon, Y. H., Lee, S., ... Kim, S. (2022). AIMP2-DX2 provides therapeutic interface to control KRAS-driven tumorigenesis. Nature Communications, 13(1), Article 2572. https://doi.org/10.1038/s41467-022-30149-2

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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.",

author = "Kim, \{Dae Gyu\} and Yongseok Choi and Yuno Lee and Semi Lim and Jiwon Kong and Song, \{Jae Ha\} and Younah Roh and Harmalkar, \{Dipesh S.\} and Kwanshik Lee and Goo, \{Ja il\} and Cho, \{Hye Young\} and Mushtaq, \{Ameeq Ul\} and Jihye Lee and Park, \{Song Hwa\} and Doyeun Kim and Min, \{Byung Soh\} and Lee, \{Kang Young\} and Jeon, \{Young Ho\} and Sunkyung Lee and Kyeong Lee and Sunghoon Kim",

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AU - Lee, Kwanshik

AU - Goo, Ja il

AU - Cho, Hye Young

AU - Mushtaq, Ameeq Ul

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AU - Park, Song Hwa

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AU - Min, Byung Soh

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N2 - 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.

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

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