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Sci. Signal., 13 September 2011
Vol. 4, Issue 190, p. ra58
[DOI: 10.1126/scisignal.2001936]

RESEARCH ARTICLES

Protein Arginine Methyltransferase 5 Regulates ERK1/2 Signal Transduction Amplitude and Cell Fate Through CRAF

Pedro Andreu-Pérez1, Rosaura Esteve-Puig1, Carlos de Torre-Minguela1*, Marta López-Fauqued1, Joan Josep Bech-Serra2, Stephan Tenbaum3, Elena R. García-Trevijano4{dagger}, Francesc Canals2, Glenn Merlino5, Matías A. Ávila4, and Juan A. Recio1{ddagger}

1 Mouse Models and Cancer Laboratory, Anatomy Pathology Department, Vall d’Hebron Research Institute, Barcelona 08035, Spain.
2 Proteomic Laboratory, Medical Oncology Research Program, Vall d’Hebron Research Institute–VHIO, Barcelona 08035, Spain.
3 Cancer Stem Cells Laboratory, Medical Oncology Research Program, Vall d’Hebron Research Institute–VHIO, Barcelona 08035, Spain.
4 Division of Hepatology and Gene Therapy, Center for Applied Medical Research, University of Navarra, Pamplona 31008, Spain.
5 Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892–4264, USA.

* Present address: Hospital Arrixaca, Murcia 30120, Spain.

{dagger} Present address: Department of Biochemistry and Molecular Biology, School of Medicine, Universidad de Valencia, Valencia 46010, Spain.

Abstract: The RAS to extracellular signal–regulated kinase (ERK) signal transduction cascade is crucial to cell proliferation, differentiation, and survival. Although numerous growth factors activate the RAS-ERK pathway, they can have different effects on the amplitude and duration of the ERK signal and, therefore, on the biological consequences. For instance, nerve growth factor, which elicits a larger and more sustained increase in ERK phosphorylation in PC12 cells than does epidermal growth factor (EGF), stimulates PC12 cell differentiation, whereas EGF stimulates PC12 cell proliferation. Here, we show that protein arginine methylation limits the ERK1/2 signal elicited by particular growth factors in different cell types from various species. We found that this restriction in ERK1/2 phosphorylation depended on methylation of RAF proteins by protein arginine methyltransferase 5 (PRMT5). PRMT5-dependent methylation enhanced the degradation of activated CRAF and BRAF, thereby reducing their catalytic activity. Inhibition of PRMT5 activity or expression of RAF mutants that could not be methylated not only affected the amplitude and duration of ERK phosphorylation in response to growth factors but also redirected the response of PC12 cells to EGF from proliferation to differentiation. This additional level of regulation within the RAS pathway may lead to the identification of new targets for therapeutic intervention.

{ddagger} To whom correspondence should be addressed. E-mail: juan.recio{at}vhir.org

Citation: P. Andreu-Pérez, R. Esteve-Puig, C. de Torre-Minguela, M. López-Fauqued, J. J. Bech-Serra, S. Tenbaum, E. R. García-Trevijano, F. Canals, G. Merlino, M. A. Ávila, J. A. Recio, Protein Arginine Methyltransferase 5 Regulates ERK1/2 Signal Transduction Amplitude and Cell Fate Through CRAF. Sci. Signal. 4, ra58 (2011).

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