title: Phosphorylated K-Ras limits cell survival by blocking Bcl-xL sensitization of inositol trisphosphate receptors.
abstract: K-Ras4B is targeted to the plasma membrane by a farnesyl modification that operates in conjunction with a polybasic domain. We characterized a farnesyl-electrostatic switch whereby protein kinase C phosphorylates K-Ras4B on serine 181 in the polybasic region and thereby induces translocation from the plasma membrane to internal membranes that include the endoplasmic reticulum (ER) and outer mitochondrial membrane. This translocation is associated with cell death. Here we have explored the mechanism of phospho-K-Ras4B toxicity and found that GTP-bound, phosphorylated K-Ras4B associates with inositol trisphosphate receptors on the ER in a Bcl-xL-dependent fashion and, in so doing, blocks the ability of Bcl-xL to potentiate the InsP3 regulated flux of calcium from ER to mitochondria that is required for efficient respiration, inhibition of autophagy, and cell survival. Thus, we have identified inositol trisphosphate receptors as unique effectors of K-Ras4B that antagonize the prosurvival signals of other K-Ras effectors.
authors.affiliation: New York University (NYU) Cancer Institute, NYU School of Medicine, New York, NY 10016.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Sung
authors.forename: Frederick D
authors.initials: FD
authors.lastname: Tsai
authors.forename: Horia
authors.initials: H
authors.lastname: Vais
authors.forename: Helen
authors.initials: H
authors.lastname: Court
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.forename: Nicole
authors.initials: N
authors.lastname: Fehrenbacher
authors.forename: J Kevin
authors.initials: JK
authors.lastname: Foskett
authors.forename: Mark R
authors.initials: MR
authors.lastname: Philips
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000502:physiology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism; D015544:Inositol 1,4,5-Trisphosphate / Q000235:genetics / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D051336:Mitochondrial Membranes / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D061987:Sf9 Cells; D018411:Spodoptera; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; D053496:Inositol 1,4,5-Trisphosphate Receptors; C117307:KRAS protein, human; D051020:bcl-X Protein; D015544:Inositol 1,4,5-Trisphosphate; D011493:Protein Kinase C; D016283:Proto-Oncogene Proteins p21(ras); D002118:Calcium
keywords: cancer; membrane protein; oncogene