ABSTRACT
The Raf polypeptides are encoded by a gene family, which directs the expression of three active Raf proteins known as A-Raf, B-Raf and c-Raf (also known as Raf-1). Raf genes encode cytosolic phosphoproteins that function as serine/threonine protein kinases. The three isoforms share a common domain structure: a kinase domain occupying the carboxyl-terminal domain (the conserved region 3, or CR3) and an amino terminal half containing two regions of high sequence homology, designated CR-1 and CR-2 (Morrison and Cutler, 1997) (Figure 1). The first conserved CR1 region is rich in cysteine residues and contains the canonical sequence C-X2-C-X9-C-X2-C, which represents a zinc finger domain. The latter is thought to be involved in binding of the protein to lipids. The other highly conserved region (CR2) is a sequence of fourteen amino acids rich in serine and threonine residues. The conserved amino terminal motifs appear to have an important negative regulatory function, as substitutions, deletions or insertions in these regions activate Raf s transforming potential. The products of the Raf genes show >75% homology in their protein kinase domains and all three possess oncogenic activity (Beck et al., 1987; Heidecker et al., 1990; Ikawa et al., 1988; Rapp et al., 1983). Despite these similarities, the genes exhibit strikingly different expression patterns in normal mouse tissues (Storm et al., 1990). The c-Raf-1 gene is ubiquitously expressed whereas A-Raf is present at high levels in epididymis, ovaries and kidneys but at low levels in all other tissues. B-Raf was originally described as abundant in neuronal tissues and testis, but is now recognized to be more widely distributed (Barnier et al.,
1995). Since c-Raf is the most studied isoform of this family, the review will focus on the role of this protein in insulin mediated signaling.
