SMYD3 links lysine methylation of MAP3K2 to Ras-driven cancer

Pawel K Mazur; Nicolas Reynoird; Purvesh Khatri; Pascal W T C Jansen; Alex W Wilkinson; Shichong Liu; Olena Barbash; Glenn S Van Aller; Michael Huddleston; Dashyant Dhanak; Peter J Tummino; Ryan G Kruger; Benjamin A Garcia; Atul J Butte; Michiel Vermeulen; Julien Sage; Or Gozani

doi:10.1038/nature13320

SMYD3 links lysine methylation of MAP3K2 to Ras-driven cancer

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

Authors

Pawel K Mazur¹, Nicolas Reynoird², Purvesh Khatri³, Pascal W T C Jansen⁴, Alex W Wilkinson⁵, Shichong Liu⁶, Olena Barbash⁷, Glenn S Van Aller⁷, Michael Huddleston⁷, Dashyant Dhanak⁸, Peter J Tummino⁷, Ryan G Kruger⁷, Benjamin A Garcia⁶, Atul J Butte⁹, Michiel Vermeulen¹⁰, Julien Sage¹, Or Gozani²

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma / enzymology
Adenocarcinoma / genetics
Adenocarcinoma / metabolism
Adenocarcinoma / pathology
Adenocarcinoma of Lung
Animals
Cell Line, Tumor
Cell Transformation, Neoplastic / genetics
Cell Transformation, Neoplastic / metabolism*
Cell Transformation, Neoplastic / pathology
Disease Models, Animal
Histone-Lysine N-Methyltransferase / metabolism*
Humans
Lung Neoplasms / enzymology
Lung Neoplasms / genetics
Lung Neoplasms / metabolism
Lung Neoplasms / pathology
Lysine / metabolism*
MAP Kinase Kinase Kinase 2 / chemistry
MAP Kinase Kinase Kinase 2 / metabolism*
MAP Kinase Kinase Kinases / chemistry
MAP Kinase Kinase Kinases / metabolism*
Methylation
Mice
Mitogen-Activated Protein Kinases / metabolism
Oncogene Protein p21(ras) / genetics
Oncogene Protein p21(ras) / metabolism*
Pancreatic Neoplasms / enzymology
Pancreatic Neoplasms / genetics
Pancreatic Neoplasms / metabolism
Pancreatic Neoplasms / pathology
Protein Phosphatase 2 / antagonists & inhibitors
Protein Phosphatase 2 / metabolism
Proto-Oncogene Proteins A-raf / metabolism
Signal Transduction

Substances

Histone-Lysine N-Methyltransferase
SMYD3 protein, human
Smyd3 protein, mouse
Proto-Oncogene Proteins A-raf
Mitogen-Activated Protein Kinases
MAP Kinase Kinase Kinase 2
MAP Kinase Kinase Kinases
MAP3K2 protein, human
Map3k2 protein, mouse
Protein Phosphatase 2
Oncogene Protein p21(ras)
Lysine

Abstract

Publication types

MeSH terms

Substances

Grants and funding