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Mini-review

A Kras-Specific Function in Cancer Initiation

Margaret P. Quinlan and Jeffrey Settleman

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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 mutations 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.

Authors

Margaret P. Quinlan

Massachusetts General Hospital Cancer Center

Jeffrey Settleman

Massachusetts General Hospital Cancer Center

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