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Mol Biol Cell. 2016 Mar 15;27(6):1026-39. doi: 10.1091/mbc.E15-07-0521. Epub 2015 Dec 10.

Intrinsically active variants of Erk oncogenically transform cells and disclose unexpected autophosphorylation capability that is independent of TEY phosphorylation.

Author information

1
Department of Biological Chemistry, Institute of Life Science, Hebrew University of Jerusalem, Jerusalem 91904, Israel Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117456.
2
Department of Biological Chemistry, Institute of Life Science, Hebrew University of Jerusalem, Jerusalem 91904, Israel.
3
Department of Biology, Technion-Israel Institute of Technology, Haifa 32000, Israel.
4
Department of Biological Chemistry, Institute of Life Science, Hebrew University of Jerusalem, Jerusalem 91904, Israel Wolfson Centre for Applied Structural Biology, Hebrew University of Jerusalem, Jerusalem 91904, Israel.
5
Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117456 CREATE-NUS-HUJ, Cellular and Molecular Mechanisms of Inflammation Program, National University of Singapore, Singapore 138602.
6
Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309.
7
Department of Biological Chemistry, Institute of Life Science, Hebrew University of Jerusalem, Jerusalem 91904, Israel Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117456 CREATE-NUS-HUJ, Cellular and Molecular Mechanisms of Inflammation Program, National University of Singapore, Singapore 138602 CREATE-NUS-HUJ, Cellular and Molecular Mechanisms of Inflammation Program, National University of Singapore, Singapore 138602.

Abstract

The receptor-tyrosine kinase (RTK)/Ras/Raf pathway is an essential cascade for mediating growth factor signaling. It is abnormally overactive in almost all human cancers. The downstream targets of the pathway are members of the extracellular regulated kinases (Erk1/2) family, suggesting that this family is a mediator of the oncogenic capability of the cascade. Although all oncogenic mutations in the pathway result in strong activation of Erks, activating mutations in Erks themselves were not reported in cancers. Here we used spontaneously active Erk variants to check whether Erk's activity per se is sufficient for oncogenic transformation. We show that Erk1(R84S) is an oncoprotein, as NIH3T3 cells that express it form foci in tissue culture plates, colonies in soft agar, and tumors in nude mice. We further show that Erk1(R84S) and Erk2(R65S) are intrinsically active due to an unusual autophosphorylation activity they acquire. They autophosphorylate the activatory TEY motif and also other residues, including the critical residue Thr-207 (in Erk1)/Thr-188 (in Erk2). Strikingly, Erk2(R65S) efficiently autophosphorylates its Thr-188 even when dually mutated in the TEY motif. Thus this study shows that Erk1 can be considered a proto-oncogene and that Erk molecules possess unusual autoregulatory properties, some of them independent of TEY phosphorylation.

PMID:
26658610
PMCID:
PMC4791124
DOI:
10.1091/mbc.E15-07-0521
[Indexed for MEDLINE]
Free PMC Article

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