(A) Representation of typical cells in which K-RAS and its two downstream arms are not activated. (B) In most tissues, including pancreatic cancer cells, activation of K-RAS results in activation of downstream targets, including the RAF/MAPK pathway, which generally drives proliferation, and the tumor-suppressor family of RASSF proteins. K-RAS activates both pathways, but the mitogenic balance swings in favor of proliferation, as occurs in pancreatic adenocarcinoma. (C) In contrast, in pancreatic endocrine β cells, K-RAS activation drives both pathways, but the mitogenic RAF/MAPK arm is inhibited by the downstream tumor suppressor menin; therefore, the proliferation-inhibiting RASSF arm tips the balance in favor of inhibition of proliferation. (D) In menin-deficient β cells, the balance swings back in favor of proliferation. For a more detailed biochemical schematic, see Figure 5J in Chamberlain et al. (1). This paradigm appears to apply to other endocrine cells such as pituitary and parathyroid cells.