Raf kinases: function, regulation and role in human cancer

Abstract

The Ras-Raf-MAPK pathway regulates diverse physiological processes by transmitting signals from membrane based receptors to various nuclear, cytoplasmic and membrane-bound targets, coordinating a large variety of cellular responses. Function of Raf family kinases has been shown to play a role during organism development, cell cycle regulation, cell proliferation and differentiation, cell survival and apoptosis and many other cellular and physiological processes. Aberrations along the Ras-Raf-MAPK pathway play an integral role in various biological processes concerning human health and disease. Overexpression or activation of the pathway components is a common indicator in proliferative diseases such as cancer and contributes to tumor initiation, progression and metastasis. In this review, we focus on the physiological roles of Raf kinases in normal and disease conditions, specifically cancer, and the current thoughts on Raf regulation.

Fig. 1

Structural alignment of Raf isoforms. The human C-Raf (Raf-1 or c-Raf-1), B-Raf and A-Raf are aligned with the Drosophila Raf (D-Raf) and C.elegans Raf (lin45). Indicated are the positions of conserved regions (CR) 1, 2 and 3, the Ras binding domain (RBD), the zinc finger/cysteine rich domain (CRD) and the kinase domain. In addition, indicated are the known phosphorylation sites on C-Raf and their corresponding sites in the other Raf isoforms, position of the ATP binding site (K375) and V600 of B-Raf found mutated in cancers.

Fig. 2

Known physiological functions of Raf. See text for details.

Fig. 3

Raf structure and sequence alignment of human Raf isoforms. A. Sequence alignment of the three human Raf isoforms. Indicated are the positions of β-sheets and α-helices, aminoacid identities (boxed, red), aminoacid identities (boxed, clear) and known C-Raf phosphorylation sites (green triangles). B. Known Raf structures. Indicated are the positions of the RBD, CRD, kinase domain and of CR1–3. The known Raf phosphorylation sites and potential kinases that can phosphorylate them are also indicated. See text for more details.

Fig. 4

Raf activation model. This is a simplistic model showing the role of Ras, 14-3-3 and potential kinases involved in Raf activation. See text for details.

Fig. 5

2-D C-Raf phosphopeptide map. An example of C-Raf phosphopeptide maps showing the positions of several known C-Raf phosphorylation sites. The identity of the mutants is indicated. Panel 1 is wildtype C-Raf. For method details see references 151 and 159. Spots 1, 2 and 3 in panel 6 represent pS43, pS621 and pS259 respectively.