ERK1 and ERK2 mitogen-activated protein kinases affect Ras-dependent cell signaling differentially

Vantaggiato, Chiara, Formentini, Ivan, Bondanza, Attilio, Bonini, Chiara, Naldini, Luigi and Brambilla, Riccardo ORCID: https://orcid.org/0000-0003-3569-5706 2006. ERK1 and ERK2 mitogen-activated protein kinases affect Ras-dependent cell signaling differentially. Journal of Biology 5 (5) , 14. 10.1186/jbiol38

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Abstract

Background: The mitogen-activated protein (MAP) kinases p44ERK1 and p42ERK2 are crucial components of the regulatory machinery underlying normal and malignant cell proliferation. A currently accepted model maintains that ERK1 and ERK2 are regulated similarly and contribute to intracellular signaling by phosphorylating a largely common subset of substrates, both in the cytosol and in the nucleus. Results: Here, we show that ablation of ERK1 in mouse embryo fibroblasts and NIH 3T3 cells by gene targeting and RNA interference results in an enhancement of ERK2-dependent signaling and in a significant growth advantage. By contrast, knockdown of ERK2 almost completely abolishes normal and Ras-dependent cell proliferation. Ectopic expression of ERK1 but not of ERK2 in NIH 3T3 cells inhibits oncogenic Ras-mediated proliferation and colony formation. These phenotypes are independent of the kinase activity of ERK1, as expression of a catalytically inactive form of ERK1 is equally effective. Finally, ectopic expression of ERK1 but not ERK2 is sufficient to attenuate Ras-dependent tumor formation in nude mice. Conclusion: These results reveal an unexpected interplay between ERK1 and ERK2 in transducing Ras-dependent cell signaling and proliferation. Whereas ERK2 seems to have a positive role in controlling normal and Ras-dependent cell proliferation, ERK1 probably affects the overall signaling output of the cell by antagonizing ERK2 activity

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
ISSN:	1475-4924
Last Modified:	27 Oct 2022 08:26
URI:	https://orca.cardiff.ac.uk/id/eprint/62307

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