Conferring specificity on the ubiquitous Raf/MEK signalling pathway

E O'Neill, W Kolch, E O'Neill, W Kolch

Abstract

The Raf-MEK-ERK signalling pathway controls fundamental cellular processes including proliferation, differentiation and survival. It remains enigmatic how this pathway can reliably convert a myriad of extracellular stimuli in specific biological responses. Recent results have shown that the Raf family isoforms A-Raf, B-Raf and Raf-1 have different physiological functions. Here we review how Raf isozyme diversity contributes to the specification of functional diversity, in particular regarding the role of Raf isozymes in cancer.

Figures

Figure 1
Figure 1
PC12 cell model of neuronal differentiation. This model shows how a biological response is specified by the kinetics and duration of ERK activity, which is achieved through the combinatorial integration of activating different Raf isoforms and crosstalk with the cAMP signalling system. PC12 cells differentiate in response to the nerve growth factor (NGF), but proliferate in response to the epidermal growth factor (EGF). Both growth factors utilise the Raf/MEK/ERK pathway. The biological response is determined by the duration of ERK signalling. Sustained ERK activation results in neuronal differentiation. The sustenance of ERK activity is caused by the B-Raf isoform, which is activated preferentially by NGF. Differentiation is further enhanced by activation of cAMP signalling, which inhibits Raf-1, but promotes B-Raf activity.
Figure 2
Figure 2
Different signalling complexes and subcellular compartmentalisation can generate diverse cellular responses. See text for details.

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