Phosphorylated K-Ras limits cell survival by blocking Bcl-xL sensitization of inositol trisphosphate receptors

K-Ras is mutated more often than any other oncogene, making the protein and the pathways it regulates attractive targets for anticancer drug discovery. We have shown that phosphorylation of serine 181 in the membrane-targeting region of K-Ras causes the protein to translocate from plasma membrane to intracellular membranes. Translocation is associated with toxicity but the mechanism has remained undefined. Here we show that phospho–K-Ras associates with inositol trisphosphate receptors (IP3Rs) on the endoplasmic reticulum (ER) and thereby blocks one of the prosurvival activities of Bcl-xL, which is to sensitize IP3Rs and thereby allow constitutive transfer of calcium from ER to mitochondria where it is required for efficient respiration. This pathway could be exploited to limit the oncogenic activity of mutant K-Ras.