SMYD3 links lysine methylation of MAP3K2 to Ras-driven cancer
Autor: | Michiel Vermeulen, Nicolas Reynoird, Julien Sage, Olena Barbash, Or Gozani, Atul J. Butte, Shichong Liu, Michael J. Huddleston, Ryan G. Kruger, Dashyant Dhanak, Purvesh Khatri, Alex W. Wilkinson, Pascal W. T. C. Jansen, Benjamin A. Garcia, Pawel K. Mazur, Peter J. Tummino, Glenn S. Van Aller |
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Přispěvatelé: | Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Universitaire [Grenoble] (CHU)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA) |
Jazyk: | angličtina |
Rok vydání: | 2014 |
Předmět: |
MAPK/ERK pathway
Methyltransferase Lung Neoplasms [SDV]Life Sciences [q-bio] Adenocarcinoma of Lung MAP3K2 Biology Adenocarcinoma MAP Kinase Kinase Kinase 2 Oncogene Protein p21(ras) Methylation Proto-Oncogene Proteins A-raf Mice Cell Line Tumor Animals Humans Protein Phosphatase 2 ComputingMilieux_MISCELLANEOUS Multidisciplinary MAP kinase kinase kinase Proteomics and Chromatin Biology MEK inhibitor Lysine Protein phosphatase 2 Histone-Lysine N-Methyltransferase MAP Kinase Kinase Kinases Research Highlight 3. Good health Pancreatic Neoplasms Disease Models Animal Cell Transformation Neoplastic Cancer research Mitogen-Activated Protein Kinases Signal Transduction |
Zdroj: | Nature Nature, Nature Publishing Group, 2014, 510 (7504), pp.283-287. ⟨10.1038/nature13320⟩ Nature, 510, 283-7 Nature, 510, 7504, pp. 283-7 |
ISSN: | 0028-0836 1476-4679 |
Popis: | Deregulation of lysine methylation signalling has emerged as a common aetiological factor in cancer pathogenesis, with inhibitors of several histone lysine methyltransferases (KMTs) being developed as chemotherapeutics. The largely cytoplasmic KMT SMYD3 (SET and MYND domain containing protein 3) is overexpressed in numerous human tumours. However, the molecular mechanism by which SMYD3 regulates cancer pathways and its relationship to tumorigenesis in vivo are largely unknown. Here we show that methylation of MAP3K2 by SMYD3 increases MAP kinase signalling and promotes the formation of Ras-driven carcinomas. Using mouse models for pancreatic ductal adenocarcinoma and lung adenocarcinoma, we found that abrogating SMYD3 catalytic activity inhibits tumour development in response to oncogenic Ras. We used protein array technology to identify the MAP3K2 kinase as a target of SMYD3. In cancer cell lines, SMYD3-mediated methylation of MAP3K2 at lysine 260 potentiates activation of the Ras/Raf/MEK/ERK signalling module and SMYD3 depletion synergizes with a MEK inhibitor to block Ras-driven tumorigenesis. Finally, the PP2A phosphatase complex, a key negative regulator of the MAP kinase pathway, binds to MAP3K2 and this interaction is blocked by methylation. Together, our results elucidate a new role for lysine methylation in integrating cytoplasmic kinase-signalling cascades and establish a pivotal role for SMYD3 in the regulation of oncogenic Ras signalling. |
Databáze: | OpenAIRE |
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