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

doi:10.1158/0008-5472.CAN-15-3255

Oncogenic Mutation of AIMP2/p38 Inhibits Its Tumor-Suppressive Interaction with Smurf2

Cancer Res. 2016 Jun 1;76(11):3422-36. doi: 10.1158/0008-5472.CAN-15-3255. Epub 2016 Apr 6.

Authors

Dae Gyu Kim¹, Jin Young Lee¹, Ji-Hyun Lee¹, Ha Yeon Cho², Beom Sik Kang², Song-Yee Jang³, Myung Hee Kim³, Min Guo⁴, Jung Min Han⁵, Seong-Jin Kim⁶, Sunghoon Kim⁷

Affiliations

¹ Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Seoul, Korea.
² School of Life Science and Biotechnology, Kyungpook National University, Daegu, Korea.
³ Infection and Immunity Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.
⁴ Department of Cancer Biology, Scripps Research Institute, Florida Campus, Jupiter, Florida.
⁵ College of Pharmacy, Yonsei University, Seoul, South Korea.
⁶ CHA Research Institutes & CHA Cancer Institute, CHA University, Seongnam, Korea.
⁷ Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Seoul, Korea. Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Korea. [email protected].

PMID: 27197155
DOI: 10.1158/0008-5472.CAN-15-3255

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 ubiquitin-mediated 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 TGFβ 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. Cancer Res; 76(11); 3422-36. ©2016 AACR.

MeSH terms

Animals
Apoptosis
Blotting, Western
Cell Proliferation
Cells, Cultured
DNA Helicases / genetics
DNA Helicases / metabolism
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism
Embryo, Mammalian / metabolism
Embryo, Mammalian / pathology*
Female
Fibroblasts / metabolism
Fibroblasts / pathology*
HeLa Cells
Humans
Immunoenzyme Techniques
Immunoprecipitation
Lung Neoplasms / genetics
Lung Neoplasms / metabolism
Lung Neoplasms / pathology*
Mice
Mice, Inbred BALB C
Mice, Knockout
Mice, Nude
Peptide Elongation Factors / genetics
Peptide Elongation Factors / metabolism*
Proto-Oncogene Proteins c-myc / genetics
Proto-Oncogene Proteins c-myc / metabolism
RNA, Messenger / genetics
RNA-Binding Proteins
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
Tumor Suppressor Proteins / genetics
Tumor Suppressor Proteins / metabolism*
Ubiquitin / metabolism
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / metabolism*
Ubiquitination
Xenograft Model Antitumor Assays
p38 Mitogen-Activated Protein Kinases / genetics
p38 Mitogen-Activated Protein Kinases / metabolism*

Substances

DNA-Binding Proteins
EEF1E1 protein, human
FUBP1 protein, human
MYC protein, human
Peptide Elongation Factors
Proto-Oncogene Proteins c-myc
RNA, Messenger
RNA-Binding Proteins
Tumor Suppressor Proteins
Ubiquitin
SMURF2 protein, human
Ubiquitin-Protein Ligases
p38 Mitogen-Activated Protein Kinases
DNA Helicases