RAS

an oncogene (v-ras) discovered in the retroviruses Harvey and Kirsten rat sarcoma viruses. There are three closely related (85% homology) oncogenes, Ha-ras, Ki-ras, and N-ras. Their cellular counterparts encode 21 kDa guanine nucleotide-binding proteins that regulate growth and differentiation in nearly every eukaryotic cell studied. There are two subfamilies, the Rho and Rac proteins (involved in relaying signals from the cell-surface receptors to the actin cytoskeleton) and the Rab family (involved in regulating the traffic of intracellular transport vesicles). Ras proteins undergo modification of the N and C termini that localize them to the plasma membrane. Ras is considered active in the GTP-bound form and inactive in the GDP-bound form. The intrinsic rate of nucleotide exchange and GTPase activity is very slow. Ras·GDP predominates in resting cells, but when Ras is activated by occupied receptors, specific guanine nucleotide exchange factors (GEFs), e.g. Sos, enhance nucleotide exchange leading to Ras·GTP, GTP exceeding GDP in cytoplasm. Ras·GTP then activates downstream effector proteins such as Raf-1 (see raf). Activated GTPase activating protein (GAP) causes the formation of inactive Ras·GDP. The retroviral oncogene, v-ras, encodes a protein that differs from the c-ras product in a single residue. If this affects amino acids 12, 13, 59, 61, or 63 the protein fails to hydrolyse its bound GTP and so persists abnormally in its active state, constitutively transmitting an intracellular signal for cell proliferation. Alternatively, some transforming mutations increase the rate at which Ras can exchange guanine nucleotides, e.g. when amino acids 116, 117, 119, or 146 are affected, again increasing the amount of Ras·GTP. Activated ras oncogenes occur in up to 30% of all human tumours, with the most common mutations being at codons for amino acids 12 and 13. In some types of malignancy, the figure is nearly 100%. Two genes corresponding to H-ras occur in yeast; they encode G-proteins that inhibit adenylate cyclase.

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