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.
Since their discovery over 20 years ago, the RAF proteins have been intensely studied. For most of that time, the focus of the field has been the C-RAF isoform and its role as an effector of the RAS proteins. However, a report that implicates B-RAF in human cancer has highlighted the importance of all members of this protein kinase family and recent studies have uncovered intriguing new data relating to their complex regulation and biological functions.
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We would like to thank M. Garnett and the other members of the Signal Transduction Team for their helpful discussions. This work is funded by The Institute of Cancer Research, Cancer Research UK and The Biotechnology and Biological Sciences Research Council.
The authors declare no competing financial interests.
Genes (or their products) that are descended from a common ancestral gene.
- SMALL G PROTEINS
Small proteins such as RAS that mediate signalling by binding and hydrolysing GTP. The GTP-bound form is active. It interacts with and activates several effector proteins that mediate downstream signalling events. The GDP-bound form is inactive.
Genes or gene families that originated from a common ancestral sequence by a duplication event, and have since followed distinct lineages. Orthologues are from the same lineage of a family (for example, A-RAF, B-RAF and C-RAF). Paralogues and orthologues are homologues.
- CYSTEINE-RICH DOMAIN
(CRD). A zinc-finger-like structure located in CR1 of RAF proteins. It forms a secondary binding site for RAS, but binds in a GTP-independent manner. This region also interacts with 14-3-3 proteins and lipids.
- INNER LEAFLET
A lipid layer that faces the inside of the cell.
Adaptor/scaffold proteins that form homo- and heterodimers. They bind, through specialized phosphorylated peptide motifs, to various proteins that are involved in signal transduction and cell-cycle control.
- ADAPTOR PROTEINS
Proteins that augment cellular responses by recruiting other proteins to a complex. They usually contain several protein–protein interaction domains.
(12,13-tetradecanoyl phorbol acetate). Also known as phorbol myristoyl acetate, this is the most commonly used phorbol ester. Phorbol esters are polycyclic esters that are isolated from croton oil. They are potent co-carcinogens or tumour promoters because they mimic diacylglycerol and thereby irreversibly activate protein kinase C.
- G-PROTEIN-COUPLED RECEPTOR
A seven-helix transmembrane-spanning cell-surface receptor that signals through heterotrimeric GTP-binding and -hydrolysing G proteins to stimulate or inhibit the activity of a downstream enzyme.
- HETEROTRIMERIC G PROTEIN
A protein complex of three proteins (Gα, Gβ and Gγ). Whereas Gβ and Gγ form a tight complex, Gα is part of the complex in its inactive, GDP-bound, form but dissociates in its active, GTP-bound, form. Both Gα and Gβγ can transmit downstream signals after activation.
- RHO-FAMILY GTPases
Ras-related GTPases involved in controlling the polymerization of actin.
- DOMINANT NEGATIVE
A defective protein that retains interaction capabilities and so distorts or competes with normal proteins.
A large family of heterodimeric transmembrane proteins that function as receptors for cell-adhesion molecules.
- ACTIVATION SEGMENT
A region in protein kinases that lies between the invariant DFG and APE motifs and that in many, but not all, kinases is the site of regulatory phosphorylation events. This is often referred to as the 'activation loop', although it sometimes does not form a loop.
- GLYCINE-RICH LOOP
A conserved glycine-rich region that is located in the amino-terminal part of protein kinase domains. It is identified by the consensus motif Gly-X-Gly-X-X-Gly (where X represents any amino acid) and functions as a flexible loop that anchors the phosphates of ATP into the catalytic cleft.
- VENTRICULAR MYOCYTES
Cells derived from heart ventricles. These cells have limited proliferative potential and are used in models of biological responses to ischaemia/reperfusion, and to study hypertrophy (cell growth without division).
- ENDOTHELIAL CELLS
Thin, flattened cells of mesoblastic origin that are arranged in a single layer. They line the blood vessels and some body cavities, such as those of the heart.
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Wellbrock, C., Karasarides, M. & Marais, R. The RAF proteins take centre stage. Nat Rev Mol Cell Biol 5, 875–885 (2004). https://doi.org/10.1038/nrm1498
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