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. Author manuscript; available in PMC: 2021 Feb 1.
Published in final edited form as: Biochim Biophys Acta Mol Cell Res. 2019 Oct 31;1867(2):118570. doi: 10.1016/j.bbamcr.2019.118570

Figure 1. RAS signaling and mutational activation in cancer.

Figure 1.

A. GTPase cycle. RAS proteins normally reside in the inactive, GDP-bound state. Mitogenic stimulation results in recruitment of GEFs to the plasma membrane and binding of RAS. This results in destabilization of nucleotide binding leading to release of GDP and creation of a transient nucleotide free state. Due to the high concentration of GTP in cells relative to GDP, RAS proteins load with GTP resulting in the switch to the active state. RAS-GTP recruits and activates a number of downstream targets, including RAF and PI3K. Termination of RAS signaling occurs through hydrolysis of GTP to GDP which is facilitated by GTPase accelerating/activating proteins that enhance the relatively poor intrinsic GTPase activity of RAS by nearly 100-fold, thereby returning RAS to the inactive, GDP-bound state. B. RAS mutation frequency in human tumors. Data were compiled from the Catalogue of Somatic Mutations (COSMIC), v86 [174]. Frequency of mutations in each RAS gene is shown in the first column. The percentage of mutations in each codon hotspot is indicated to the right of each gene. The frequency of the top three most prevalent amino acid substitutions at the indicated codon is indicated below the mutation frequency for that codon hotspot. These mutational hot spots all reside in the effector lobe of RAS.