Increasing complexity of the Ras signaling pathway.

Ras is a key regulator of cell growth in all eukaryotic cells. Genetic, biochemical, and molecular studies in Caenorhabditis elegans, Drosophila, and mammalian cells have positioned Ras centrally in signal transduction pathways that respond to diverse extracellular stimuli, including peptide growth factors, cytokines, and hormones. The biological activity of Ras is controlled by a regulated GDP/GTP cycle. Guanine nucleotide exchange factors (GEFs; RasGRF1/2 and Sos1/2) promote the formation of the active, GTP-bound form of Ras (1). GTPaseactivating proteins (GAPs; p120 GAP and NF1) accelerate the intrinsic GTP hydrolytic activity of Ras to promote formation of the inactive, GDP-bound form of Ras (1). Mutations in Ras at amino acids 12, 13, or 61 make Ras insensitive to GAP action and, hence, constitutively active in transforming mammalian cells (2, 3). These activating mutations in Ras are prevalent in a wide spectrum of human cancers. It has been estimated that 30% of all human tumors contain an activating mutation in Ras. The frequency of Ras mutations varies depending on tumor type, with the highest frequencies seen in lung, colon, thyroid, and pancreatic carcinomas (3). The frequency of Ras mutations is likely to be an underestimation of the contribution of aberrant signaling through the Ras pathway to human malignancies because chronic up-regulation of the Ras pathway can occur in the absence of mutations in Ras itself (4–6).