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Nature. 2014 Jun 12;510(7504):283-7. doi: 10.1038/nature13320. Epub 2014 May 21.

SMYD3 links lysine methylation of MAP3K2 to Ras-driven cancer.

Author information

1
1] Department of Pediatrics, Stanford University School of Medicine, California 94305, USA [2] Department of Genetics, Stanford University School of Medicine, California 94305, USA [3].
2
1] Department of Biology, Stanford University, California 94305, USA [2].
3
Institute for Immunity, Transplantation and Infection, and Department of Medicine, Stanford University School of Medicine, California 94305, USA.
4
Department of Molecular Cancer Research and Department of Medical Oncology, University Medical Center Utrecht, 3508 AB Utrecht, The Netherlands.
5
Department of Biology, Stanford University, California 94305, USA.
6
Epigenetics Program and Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
7
Cancer Epigenetics DPU, Oncology R&D, GlaxoSmithKline, Collegeville, Pennsylvania 19426 USA.
8
1] Cancer Epigenetics DPU, Oncology R&D, GlaxoSmithKline, Collegeville, Pennsylvania 19426 USA [2] Janssen Research and Development, 1400 McKean Road, Spring House, Pennsylvania 19477, USA (D.D.); Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University, 6525GA Nijmegen, The Netherlands (M.V.).
9
1] Department of Pediatrics, Stanford University School of Medicine, California 94305, USA [2] Department of Genetics, Stanford University School of Medicine, California 94305, USA.
10
1] Department of Molecular Cancer Research and Department of Medical Oncology, University Medical Center Utrecht, 3508 AB Utrecht, The Netherlands [2] Janssen Research and Development, 1400 McKean Road, Spring House, Pennsylvania 19477, USA (D.D.); Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University, 6525GA Nijmegen, The Netherlands (M.V.).

Abstract

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.

PMID:
24847881
PMCID:
PMC4122675
DOI:
10.1038/nature13320
[Indexed for MEDLINE]
Free PMC Article

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