[A Kras-specific function in cancer initiation].

The three closely related Ras proteins, Kras, Hras and Nras constitute the founding members of the Ras superfamily of small GTPases, which serve as molecular switches that relay extracellular signals to a variety of fundamental cellular processes, including proliferation, survival and differentiation. 1,2 These proteins have been of particular interest to cancer biologists due to the high frequency with which the genes encoding them undergo mutational activation in human cancer. 2,3 Thus, ~30% of all human tumors harbor mutations in Ras genes, as well as mutations in a variety of additional Ras pathway components. 4 Ras GTPase signaling is normally self‑limiting due to GTP‑hydrolysis, which results in the inactivation of the protein, and this property is disrupted upon oncogenic activation due to the fact that the mutations give rise to Ras proteins that remain " locked " in a GTP‑bound, active form, resulting in sustained and inappropriate downstream signaling. Despite the natural occurrence of constitutively activating muta‑ tions in each of the three Ras genes, mutationally activated Kras is found, by far, at the greatest frequency, occurring in 17–25% of all human tumors. The bias toward Kras involvement in human carcinogenesis seems somewhat surprising when considering that significant efforts over many years to compare their properties have failed to reveal obvious differences in their biochemical and functional properties, at least in vitro. Furthermore, all three Ras proteins interface with a plethora of common effector proteins and a clear discrimination among the Ras isoforms in these interactions has not emerged. The constitutively active forms of each of the three Ras isoforms are able to promote the oncogenic transformation of NIH3T3 fibroblasts. Curiously, Hras has long been considered the most potent ras oncogene, probably reflecting its striking activity in NIH3T3 cells, and has consequently been the most studied Ras isoform. The amino acid sequences of the three major Ras isoforms are nearly identical for 85% of the protein length; whereas, the carboxyl‑termini, which determine their post translational modification by lipids and consequent subcellular membrane distribution, are encoded by a so‑called hypervariable region, and thus are likely contribute to their distinct oncogenic potential in vivo, most likely by affecting the strength and/or duration of interactions with their downstream effectors. Interestingly, Kras mutations are detected with highest frequency in pancreas (85%), lung (35%) and colorectal (30%). These tissues are complex and composed of various differentiated cell types that contribute to specialized functions. However, these …