The 21 kDa guanine-nucleotide binding proteins (K-Ras, H-Ras and N-Ras) cycle between active (GTPbound) and inactive (GDP-bound) forms (1). Receptor tyrosine kinases and G-protein-coupled receptors activate Ras, which then stimulates the Raf-MEK-MAPK pathway (2-4). GTPase-activating proteins (GAP) normally facilitate the inactivation of Ras. However, in 30% of human tumors, point mutations in Ras prevent the GAP-mediated inhibition of this pathway (5). The most common oncogenic Ras mutation found in tumors is Gly12 to Asp (G12D), which prevents Ras inactivation, possibly by increasing the overall rigidity of the protein (5,6).
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