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 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.
authors.affiliation: Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Seoul, Korea.
authors.forename: Dae Gyu
authors.initials: DG
authors.lastname: Kim
authors.affiliation: Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Seoul, Korea.
authors.forename: Jin Young
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Seoul, Korea.
authors.forename: Ji-Hyun
authors.initials: JH
authors.lastname: Lee
authors.affiliation: School of Life Science and Biotechnology, Kyungpook National University, Daegu, Korea.
authors.forename: Ha Yeon
authors.initials: HY
authors.lastname: Cho
authors.affiliation: School of Life Science and Biotechnology, Kyungpook National University, Daegu, Korea.
authors.forename: Beom Sik
authors.initials: BS
authors.lastname: Kang
authors.affiliation: Infection and Immunity Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.
authors.forename: Song-Yee
authors.initials: SY
authors.lastname: Jang
authors.affiliation: Infection and Immunity Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.
authors.forename: Myung Hee
authors.initials: MH
authors.lastname: Kim
authors.affiliation: Department of Cancer Biology, Scripps Research Institute, Florida Campus, Jupiter, Florida.
authors.forename: Min
authors.initials: M
authors.lastname: Guo
authors.affiliation: College of Pharmacy, Yonsei University, Seoul, South Korea.
authors.forename: Jung Min
authors.initials: JM
authors.lastname: Han
authors.affiliation: CHA Research Institutes & CHA Cancer Institute, CHA University, Seongnam, Korea.
authors.forename: Seong-Jin
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: 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. sungkim@snu.ac.kr.
authors.forename: Sunghoon
authors.initials: S
authors.lastname: Kim
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D006367:HeLa Cells; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008819:Mice, Nude; D010445:Peptide Elongation Factors / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D016601:RNA-Binding Proteins; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C529799:EEF1E1 protein, human; C492258:FUBP1 protein, human; C489427:MYC protein, human; D010445:Peptide Elongation Factors; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; C471641:SMURF2 protein, human; D044767:Ubiquitin-Protein Ligases; D048051:p38 Mitogen-Activated Protein Kinases; D004265:DNA Helicases