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


CONCLUSIONS
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.
Vantaggiato
Chiara
C
Istituto Scientifico San Raffaele and Università Vita-Salute San Raffaele, Via Olgettina 58, 20132 Milano, Italy.|Current address: Istituto Scientifico E. Medea, 23848 Bosisio Parini, Italy.
Formentini
Ivan
I
Istituto Scientifico San Raffaele and Università Vita-Salute San Raffaele, Via Olgettina 58, 20132 Milano, Italy.
Bondanza
Attilio
A
Istituto Scientifico San Raffaele and Università Vita-Salute San Raffaele, Via Olgettina 58, 20132 Milano, Italy.
Bonini
Chiara
C
Istituto Scientifico San Raffaele and Università Vita-Salute San Raffaele, Via Olgettina 58, 20132 Milano, Italy.
Naldini
Luigi
L
Istituto Scientifico San Raffaele and Università Vita-Salute San Raffaele, Via Olgettina 58, 20132 Milano, Italy.
Brambilla
Riccardo
R
Istituto Scientifico San Raffaele and Università Vita-Salute San Raffaele, Via Olgettina 58, 20132 Milano, Italy.
D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D004789:Enzyme Activation; D020868:Gene Silencing; D051379:Mice; D008819:Mice, Nude; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D011485:Protein Binding; D015398:Signal Transduction; D014162:Transfection; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases; D018631:ras Proteins