Research ArticleCell Biology

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

Sci. Signal.  13 Sep 2011:
Vol. 4, Issue 190, pp. ra58
DOI: 10.1126/scisignal.2001936

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Minimized by Methylation

Many growth factors signal through the RAS to RAF to extracellular signal–regulated kinase (RAS-ERK) cascade, a signaling pathway that involves the sequential phosphorylation and activation of a series of protein kinases. Despite their common activation of RAS-ERK signaling, however, different growth factors elicit distinct biological responses. For instance, nerve growth factor (NGF) stimulates differentiation of PC12 cells, whereas epidermal growth factor (EGF) stimulates PC12 cell proliferation. Andreu-Pérez et al. found that the amplitude and duration of ERK phosphorylation in response to certain growth factors are kept in check by methylation of activated RAF proteins, a modification that enhanced RAF protein degradation and thereby limited downstream signaling in the RAS-ERK pathway. When RAF methylation was prevented experimentally, the amplitude and duration of the ERK signal elicited by EGF in PC12 cells (normally smaller and briefer than that elicited by NGF) increased, and the biological response switched from proliferation to differentiation.