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J Biol. 2006;5(5):14. doi: 10.1186/jbiol38.

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

Author information

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.
#
Contributed equally

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.

PMID:
16805921
PMCID:
PMC1781522
DOI:
10.1186/jbiol38
[Indexed for MEDLINE]
Free PMC Article

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