Oncogenic mutation of AIMP2/p38 inhibits its tumor-suppressive interaction with Smurf2
Dae Gyu Kim, Jin Young Lee, Ji Hyun Lee, Ha Yeon Cho, Beom Sik Kang, Song Yee Jang, Myung Hee Kim, Min Guo, Jung Min Han, Seong Jin Kim, Sunghoon Kim
Interdisciplinary Program of Integrated OMICS for Biomedical Sciences
AIMP2/p38 is a multifunctional tumor suppressor that normally resides in the cytosol as a scaffold protein of the multi-tRNA synthetase complex (MSC). One of the tumor-suppressive functions of AIMP2 is to facilitate ubiquitinmediated degradation of FUSE-binding protein (FBP, FUBP1), a transcriptional activator of c-Myc. However, the mechanism by which AIMP2 functions within this pathway and its significance in tumorigenesis are uncertain. Here, we report that Smurf2 is responsible for AIMP2-mediated ubiquitination of FBP, and a mutation in AIMP2 that inhibited its nuclear interaction with Smurf2 enhanced cellular transformation and tumorigenesis in vivo. Treatment of HeLa cells with TGFb resulted in the phosphorylation of AIMP2 on S156, a residue that is exposed on the embedded GST domain of AIMP2. We further found that phospho-AIMP2 dissociated from the MSC and translocated to the nucleus, where it bound to Smurf2, enhancing ubiquitination of FBP. AIMP2 also inhibited nuclear export of Smurf2 to sustain TGFβ signaling. Collectively, these findings present a novel tumor-suppressive interaction between AIMP2 and Smurf2 and suggest that the disruption of this interaction can lead to oncogenic transformation.
https://doi.org/10.1158/0008-5472.CAN-15-3255
Published - 2016 Jun 1
This work was supported by the Global Frontier Project grant (NRF-M3A6A4-2010-0029785 and NRF-2013M3A6A4045813) of National Research Foundation funded by the Ministry of Science, ICT and Future Planning (MSIP) of Korea, a grant from Gyeonggi Research Development Program. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
©2016 AACR.
10.1158/0008-5472.CAN-15-3255
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Amino Acyl-tRNA Synthetases Medicine & Life Sciences 100%
Ubiquitination Medicine & Life Sciences 78%
Cell Nucleus Active Transport Medicine & Life Sciences 42%
HeLa Cells Medicine & Life Sciences 36%
Cytosol Medicine & Life Sciences 34%
Kim, D. G., Lee, J. Y., Lee, J. H., Cho, H. Y., Kang, B. S., Jang, S. Y., Kim, M. H., Guo, M., Han, J. M., Kim, S. J., & Kim, S. (2016). Oncogenic mutation of AIMP2/p38 inhibits its tumor-suppressive interaction with Smurf2. Cancer Research, 76(11), 3422-3436. https://doi.org/10.1158/0008-5472.CAN-15-3255
Kim, Dae Gyu ; Lee, Jin Young ; Lee, Ji Hyun ; Cho, Ha Yeon ; Kang, Beom Sik ; Jang, Song Yee ; Kim, Myung Hee ; Guo, Min ; Han, Jung Min ; Kim, Seong Jin ; Kim, Sunghoon. / Oncogenic mutation of AIMP2/p38 inhibits its tumor-suppressive interaction with Smurf2. In: Cancer Research. 2016 ; Vol. 76, No. 11. pp. 3422-3436.
@article{6a037d983d0647e5b7dbd8f8467ee88a,
title = "Oncogenic mutation of AIMP2/p38 inhibits its tumor-suppressive interaction with Smurf2",
abstract = "AIMP2/p38 is a multifunctional tumor suppressor that normally resides in the cytosol as a scaffold protein of the multi-tRNA synthetase complex (MSC). One of the tumor-suppressive functions of AIMP2 is to facilitate ubiquitinmediated degradation of FUSE-binding protein (FBP, FUBP1), a transcriptional activator of c-Myc. However, the mechanism by which AIMP2 functions within this pathway and its significance in tumorigenesis are uncertain. Here, we report that Smurf2 is responsible for AIMP2-mediated ubiquitination of FBP, and a mutation in AIMP2 that inhibited its nuclear interaction with Smurf2 enhanced cellular transformation and tumorigenesis in vivo. Treatment of HeLa cells with TGFb resulted in the phosphorylation of AIMP2 on S156, a residue that is exposed on the embedded GST domain of AIMP2. We further found that phospho-AIMP2 dissociated from the MSC and translocated to the nucleus, where it bound to Smurf2, enhancing ubiquitination of FBP. AIMP2 also inhibited nuclear export of Smurf2 to sustain TGFβ signaling. Collectively, these findings present a novel tumor-suppressive interaction between AIMP2 and Smurf2 and suggest that the disruption of this interaction can lead to oncogenic transformation.",
author = "Kim, {Dae Gyu} and Lee, {Jin Young} and Lee, {Ji Hyun} and Cho, {Ha Yeon} and Kang, {Beom Sik} and Jang, {Song Yee} and Kim, {Myung Hee} and Min Guo and Han, {Jung Min} and Kim, {Seong Jin} and Sunghoon Kim",
note = "Funding Information: This work was supported by the Global Frontier Project grant (NRF-M3A6A4-2010-0029785 and NRF-2013M3A6A4045813) of National Research Foundation funded by the Ministry of Science, ICT and Future Planning (MSIP) of Korea, a grant from Gyeonggi Research Development Program. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Publisher Copyright: {\textcopyright}2016 AACR.",
doi = "10.1158/0008-5472.CAN-15-3255",
journal = "Cancer Research",
Kim, DG, Lee, JY, Lee, JH, Cho, HY, Kang, BS, Jang, SY, Kim, MH, Guo, M, Han, JM, Kim, SJ & Kim, S 2016, 'Oncogenic mutation of AIMP2/p38 inhibits its tumor-suppressive interaction with Smurf2', Cancer Research, vol. 76, no. 11, pp. 3422-3436. https://doi.org/10.1158/0008-5472.CAN-15-3255
Oncogenic mutation of AIMP2/p38 inhibits its tumor-suppressive interaction with Smurf2. / Kim, Dae Gyu; Lee, Jin Young; Lee, Ji Hyun; Cho, Ha Yeon; Kang, Beom Sik; Jang, Song Yee; Kim, Myung Hee; Guo, Min; Han, Jung Min; Kim, Seong Jin; Kim, Sunghoon.
In: Cancer Research, Vol. 76, No. 11, 01.06.2016, p. 3422-3436.
T1 - Oncogenic mutation of AIMP2/p38 inhibits its tumor-suppressive interaction with Smurf2
AU - Kim, Dae Gyu
AU - Lee, Jin Young
AU - Lee, Ji Hyun
AU - Cho, Ha Yeon
AU - Kang, Beom Sik
AU - Jang, Song Yee
AU - Kim, Myung Hee
AU - Guo, Min
AU - Han, Jung Min
AU - Kim, Seong Jin
AU - Kim, Sunghoon
N1 - Funding Information: This work was supported by the Global Frontier Project grant (NRF-M3A6A4-2010-0029785 and NRF-2013M3A6A4045813) of National Research Foundation funded by the Ministry of Science, ICT and Future Planning (MSIP) of Korea, a grant from Gyeonggi Research Development Program. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Publisher Copyright: ©2016 AACR.
N2 - AIMP2/p38 is a multifunctional tumor suppressor that normally resides in the cytosol as a scaffold protein of the multi-tRNA synthetase complex (MSC). One of the tumor-suppressive functions of AIMP2 is to facilitate ubiquitinmediated degradation of FUSE-binding protein (FBP, FUBP1), a transcriptional activator of c-Myc. However, the mechanism by which AIMP2 functions within this pathway and its significance in tumorigenesis are uncertain. Here, we report that Smurf2 is responsible for AIMP2-mediated ubiquitination of FBP, and a mutation in AIMP2 that inhibited its nuclear interaction with Smurf2 enhanced cellular transformation and tumorigenesis in vivo. Treatment of HeLa cells with TGFb resulted in the phosphorylation of AIMP2 on S156, a residue that is exposed on the embedded GST domain of AIMP2. We further found that phospho-AIMP2 dissociated from the MSC and translocated to the nucleus, where it bound to Smurf2, enhancing ubiquitination of FBP. AIMP2 also inhibited nuclear export of Smurf2 to sustain TGFβ signaling. Collectively, these findings present a novel tumor-suppressive interaction between AIMP2 and Smurf2 and suggest that the disruption of this interaction can lead to oncogenic transformation.
AB - AIMP2/p38 is a multifunctional tumor suppressor that normally resides in the cytosol as a scaffold protein of the multi-tRNA synthetase complex (MSC). One of the tumor-suppressive functions of AIMP2 is to facilitate ubiquitinmediated degradation of FUSE-binding protein (FBP, FUBP1), a transcriptional activator of c-Myc. However, the mechanism by which AIMP2 functions within this pathway and its significance in tumorigenesis are uncertain. Here, we report that Smurf2 is responsible for AIMP2-mediated ubiquitination of FBP, and a mutation in AIMP2 that inhibited its nuclear interaction with Smurf2 enhanced cellular transformation and tumorigenesis in vivo. Treatment of HeLa cells with TGFb resulted in the phosphorylation of AIMP2 on S156, a residue that is exposed on the embedded GST domain of AIMP2. We further found that phospho-AIMP2 dissociated from the MSC and translocated to the nucleus, where it bound to Smurf2, enhancing ubiquitination of FBP. AIMP2 also inhibited nuclear export of Smurf2 to sustain TGFβ signaling. Collectively, these findings present a novel tumor-suppressive interaction between AIMP2 and Smurf2 and suggest that the disruption of this interaction can lead to oncogenic transformation.
U2 - 10.1158/0008-5472.CAN-15-3255
DO - 10.1158/0008-5472.CAN-15-3255
JO - Cancer Research
JF - Cancer Research
Kim DG, Lee JY, Lee JH, Cho HY, Kang BS, Jang SY et al. Oncogenic mutation of AIMP2/p38 inhibits its tumor-suppressive interaction with Smurf2. Cancer Research. 2016 Jun 1;76(11):3422-3436. https://doi.org/10.1158/0008-5472.CAN-15-3255