Ras genes encode a family of proteins (all of about 21 kilodaltons) with regions homologous to sequences in the subunit of G proteins (see here). Like the subunit, the Ras proteins bind guanine nucleotides. Normal Ras proteins possess a GTPase activity, as do G proteins, whereas most ras oncogene proteins lack this activity (by convention, the name of the gene is italicized, and the corresponding protein is not). The GTPase activity suggested that normal Ras proteins function like G proteins in regulating metabolism. A mutation in the twelfth codon of the human ras oncogene that changes a glycine codon to a valine codon eliminates the protein's ability to hydrolyze GTP to GDP. In 1988, the three-dimensional structure of a Ras protein, crystallized with GDP was determined. Amino acid residues known to be changed in mutations that generate ras oncogenes are positioned close to the bound guanine nucleotide. This positioning supports the idea that interactions between the proto-oncogene Ras protein and guanine nucleotides are important to metabolic control and that this control is lost when a normal cell is transformed to a cancer cell.

A major difference between Ras-type proteins and the related G proteins is the far higher GTPase activity of the G proteins. A set of Ras-activating proteins is required to stimulate the GTPase activity of Ras. G, but not Ras, proteins contain a conserved arginine residue (R178), which stabilizes the negative charge on the phosphate of bound GTP.

The Ras protein occupies a central role in directing extracellular signals to the nucleus, where specific genes are activated for cell growth, division, and differentiation. Ras-related proteins have been discovered in such diverse organisms as yeast, nematode worms, and Drosophila, in which they control aspects of mitotic and meiotic growth and embryonic development. Research on these organisms has illuminated a central control pathway in mammalian cells (Figure 23.23), in the process richly justifying the use of simple biological model systems for cancer research.

Many growth factor receptors with tyrosine kinase activity phosphorylate themselves (steps 1 and 2 in Figure 23.23). In the phosphorylated state, each receptor interacts with one or more protein exchange factors, which in turn activate Ras by stimulating the GDP-GTP exchange (step 3). Also interacting with Ras, and limiting its activity, are proteins called LGAPs (GTPase-activating proteins). Ras activates a cascade of further protein phosphorylations (step 4), which ultimately activates transcription factors (step 5). These factors interact with the genome and stimulate the expression of particular genes (see here and here).

1. Tumor Gene Database

2. Ras