The RAF proteins take centre stage

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Abstract
C-RAF was the first of three RAF isoforms to be discovered over 20 years ago and its function and regulation have been studied in detail. RAF kinases have an important role in the regulation of cell growth, differentiation and survival and, in 2002, B-RAF was identified as a human oncogene that is mutated in approximately 7% of human cancers. All three RAF isoforms — A-RAF, B-RAF and C-RAF — are protein kinases which are activated by the binding of small G proteins of the RAS family to the N-terminal region of the RAF proteins. Phosphorylation is important in RAF regulation and, following its binding to RAS, C-RAF is recruited to the plasma membrane where dephosphorylation of negative regulatory sites and phosphorylation of positive regulatory sites cooperate to stimulate its kinase activity. For full activation, C-RAF must be phosphorylated on four sites and these sites seem to be the targets of at least three different kinases, which makes its activation a highly complex process. By contrast, B-RAF only requires phosphorylation on two sites for activation, so its activation is relatively simple. The recently resolved crystal structure of B-RAF explains why phosphorylation of the activation segment is required and also explains how oncogenic mutations in the kinase domain result in a constitutive kinase activity. The main downstream substrates of RAF kinases are MEK1 and MEK2 (mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK) kinase-1 and -2). MEK1 and MEK2, in turn, phosphorylate and activate ERK1 and ERK2. We argue that B-RAF is the main kinase that is responsible for coupling RAS to MEK, whereas C-RAF seems to have other, MEK-independent, functions, especially in the regulation of apoptosis. Other C-RAF effectors, such as apoptosis signal-regulating kinase-1 (ASK1) or BCL2-associated athanogene-1 (BAG1), are discussed. As RAF proteins influence cell growth, survival and differentiation, the regulation of their biological functions is very complex and is modulated on a number of levels. They are activated by different extracellular stimuli and fine-tuning of their functions can be achieved by subtle modulation of their activity both temporally and spatially.