20.11: The Ras Gene
The Ras gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
Ras is a superfamily of small GTPase proteins that facilitate the transmission of signals by continually cycling between an active GTP-bound form and an inactive GDP-bound form, thereby acting as molecular switches. The exchange of GDP with GTP, facilitated by the guanine nucleotide exchange factors or GEFs, turns ‘on’ the Ras proteins. The GTPase-activating proteins or GAPs catalyze the hydrolysis of GTP to GDP, turning ‘off’ the Ras proteins. An active Ras-GTP binds and activates its downstream effector molecules involved in cell growth and proliferation signaling.
Some specific point mutations, such as in codons 12, 13, or 61 in the Ras genes, result in the production of significantly impaired proteins. These mutations can affect the overall GTPase activity in the Ras proteins or impair the GAP sensitivity of the proteins. The absence of GTP hydrolysis locks the proteins into a constitutively active state. The mutant Ras proteins continually transmit signals to downstream effector molecules in the pathway, even in the absence of external stimuli, triggering the uncontrolled proliferation of cells.
Ras mutations can be found in up to 30 percent of all the human tumors screened, most commonly in colorectal carcinoma, non-small cell lung carcinoma, and pancreatic ductal adenocarcinoma. Mutations in K-ras locus are found in about 25-30 percent of tumor samples, N-ras mutations in about 8 percent of tumors, and H-ras mutations in only about 3 percent of tumors.