Cell Signaling

Getting the Message

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Science  16 Sep 2011:
Vol. 333, Issue 6049, pp. 1551
DOI: 10.1126/science.333.6049.1551-b

Cells have a limited number of biochemical signaling pathways and thus have to use the same pathway to produce strikingly different biological outcomes. Andreu-Pérez et al. report a mechanism that allows cultured PC-12 cells (derived from rat brain cells) to respond to epidermal growth factor (EGF) by proliferating, but to respond to nerve growth factor (NGF) by differentiating. Both growth factors activate a cascade of protein kinases that begins with the protein kinase Raf and ends with activation of extracellular signal–regulated protein kinases (ERKs). The authors' results indicate that, in response to EGF, the strength and duration of signaling through ERKs are limited because the enzyme protein arginine-methyltransferase 5 (PRMT5) is activated and methylates Raf proteins, causing them to be more rapidly degraded in the cell. These events were missing in cells treated with NGF, in which PRMT5 was not activated. If methylation of Raf proteins was blocked by inactivation of PRMT5 or by expression of a Raf protein engineered to lack a site for methylation, EGF in fact created stronger, more prolonged signaling through ERK that produced differentiation rather than proliferation. Thus, protein methylation is another mechanism by which signaling pathways can be modulated to produce different outcomes.

Sci. Signal. 4, ra58 (2011).

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