RAS superfamily comprises around 50 related genes encoding GTP-binding domain (G-proteins) involved in signal transduction. The main genes are HRAS, NRAS and KRAS. Ras proteins are membrane-bound GTPases. The inactive form is GDP-bound. They are activated by ligand-binding receptor tyrosine kinases such as EGFR, PDGFR, colony-stimulating factor and fibroblast growth factor. These kinases transiently convert RAS-GDP to RAS-GTP, the active form of RAS. Single amino acid substitutions can activate RAS making it highly oncogenic. Such mutations generally reduce the GTPase activity of RAS, prolonging it in its active GTP-bound form. The consequence of this is sustained activation of the RAF1-MAPK signalling pathway. RAS mutations are found in 10-15% of tumours. A high incidence of RAS mutations is found in pancreatic cancers.
