title: Post-translational modification of HINT1 mediates activation of MITF transcriptional activity in human melanoma cells.
abstract: Microphthalmia transcription factor (MITF) is a basic helix-loop-helix leucine zipper (bHLH-Zip) DNA-binding protein. This transcription factor plays a crucial role in the physiological and pathological functions of distinct cell types. MITF transcriptional activity is inhibited by the histidine triad nucleotide-binding protein 1 (HINT1) through direct binding. We previously reported that this association is disrupted by the binding of the second messenger Ap4A to HINT1. Ap4A is mainly produced in the mammalian cells by S207-phosphorylated Lysyl-tRNA synthetase. In this study, we found first that HINT1 was subjected to K21 acetylation and Y109 phosphorylation in activated mast cells, together with the Ap4A-triggered HINT1 dissociation from MITF. Mutational analysis confirmed that these modifications promote MITF transcriptional and oncogenic activity in melanoma cell lines, derived from human melanoma patients. Thus, we provided here an example that manipulation of the LysRS-Ap4A-HINT1-MITF signalling pathway in melanoma through post-translational modifications of HINT1 can affect the activity of the melanoma oncogene MITF.
authors.affiliation: Department of Biochemistry and Molecular Biology, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: A
authors.initials: A
authors.lastname: Motzik
authors.affiliation: Department of Biochemistry and Molecular Biology, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: E
authors.initials: E
authors.lastname: Amir
authors.affiliation: Department of Biochemistry and Molecular Biology, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: T
authors.initials: T
authors.lastname: Erlich
authors.affiliation: State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.affiliation: Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Seoul, South Korea.
authors.forename: B-G
authors.initials: BG
authors.lastname: Kim
authors.affiliation: Department of Integrated OMICS for Biomedical Science, Yonsei University, Seoul, South Korea.|Department of Molecular Medicine and Biopharmaceutical Sciences, Seoul National University, Seoul, South Korea.
authors.forename: J M
authors.initials: JM
authors.lastname: Han
authors.affiliation: College of Pharmacy, Yonsei University, Seoul, South Korea.
authors.forename: J H
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Oncology Department, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: H
authors.initials: H
authors.lastname: Nechushtan
authors.affiliation: Department of Cancer Biology, The Scripps Research Institute, Jupiter, FL, USA.
authors.forename: M
authors.initials: M
authors.lastname: Guo
authors.affiliation: Department of Biochemistry and Molecular Biology, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: E
authors.initials: E
authors.lastname: Razin
authors.affiliation: Department of Nuclear Medicine, Kaplan Medical Center, Rehovot, Israel.
authors.forename: S
authors.initials: S
authors.lastname: Tshori
mesh_terms: D000107:Acetylation; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics / Q000378:metabolism; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D008407:Mast Cells / Q000378:metabolism; D008545:Melanoma / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: C032578:AP4A binding protein, human; D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C063306:HINT1 protein, human; C497234:MITF protein, human; D008565:Membrane Proteins; D051739:Microphthalmia-Associated Transcription Factor; D009419:Nerve Tissue Proteins; C110546:TYROBP protein, human; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2