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

Karina Smorodinsky-Atias, Tal Goshen-Lago, Anat Goldberg-Carp, Dganit Melamed, Alexei Shir, Navit Mooshayef, Jonah Beenstock, Yael Karamansha, Ilona Darlyuk-Saadon, Oded Livnah, Natalie G. Ahn, Arie Admon, David Engelberg*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

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 Erks 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.

Original languageAmerican English
Pages (from-to)1026-1039
Number of pages14
JournalMolecular Biology of the Cell
Volume27
Issue number6
DOIs
StatePublished - 15 Mar 2016

Bibliographical note

Publisher Copyright:
© 2016 Smorodinsky-Atias, Goshen-Lago, et al.

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