Research article

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

Chiara Vantaggiato^1,2* , Ivan Formentini^1* , Attilio Bondanza¹ , Chiara Bonini¹ , Luigi Naldini¹ and Riccardo Brambilla¹

¹  Istituto Scientifico San Raffaele and Università Vita-Salute San Raffaele, Via Olgettina 58, 20132 Milano, Italy

²  Current address: Istituto Scientifico E. Medea, 23848 Bosisio Parini, Italy

author email corresponding author email* Contributed equally

Journal of Biology 2006, 5:14doi:10.1186/jbiol38

Published:	28 June 2006

Abstract

Background

The mitogen-activated protein (MAP) kinases p44^ERK1 and p42^ERK2 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.