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

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11 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)3422-3436
Number of pages15
JournalCancer Research
Volume76
Issue number11
DOIs
Publication statusPublished - 2016 Jun 1

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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    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