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

Authors :
Mazur PK
Reynoird N
Khatri P
Jansen PW
Wilkinson AW
Liu S
Barbash O
Van Aller GS
Huddleston M
Dhanak D
Tummino PJ
Kruger RG
Garcia BA
Butte AJ
Vermeulen M
Sage J
Gozani O
Source :
Nature [Nature] 2014 Jun 12; Vol. 510 (7504), pp. 283-7. Date of Electronic Publication: 2014 May 21.
Publication Year :
2014

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.

Details

Language :
English
ISSN :
1476-4687
Volume :
510
Issue :
7504
Database :
MEDLINE
Journal :
Nature
Publication Type :
Academic Journal
Accession number :
24847881
Full Text :
https://doi.org/10.1038/nature13320