title: Binding of ras to phosphoinositide 3-kinase p110alpha is required for ras-driven tumorigenesis in mice.
abstract: Ras proteins signal through direct interaction with a number of effector enzymes, including type I phosphoinositide (PI) 3-kinases. Although the ability of Ras to control PI 3-kinase has been well established in manipulated cell culture models, evidence for a role of the interaction of endogenous Ras with PI 3-kinase in normal and malignant cell growth in vivo has been lacking. Here we generate mice with mutations in the Pi3kca gene encoding the catalytic p110alpha isoform that block its interaction with Ras. Cells from these mice show proliferative defects and selective disruption of signaling from growth factors to PI 3-kinase. The mice display defective development of the lymphatic vasculature, resulting in perinatal appearance of chylous ascites. Most importantly, they are highly resistant to endogenous Ras oncogene-induced tumorigenesis. The interaction of Ras with p110alpha is thus required in vivo for certain normal growth factor signaling and for Ras-driven tumor formation.
authors.affiliation: Signal Transduction Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
authors.forename: Surbhi
authors.initials: S
authors.lastname: Gupta
authors.forename: Antoine R
authors.initials: AR
authors.lastname: Ramjaun
authors.forename: Paula
authors.initials: P
authors.lastname: Haiko
authors.forename: Yihua
authors.initials: Y
authors.lastname: Wang
authors.forename: Patricia H
authors.initials: PH
authors.lastname: Warne
authors.forename: Barbara
authors.initials: B
authors.lastname: Nicke
authors.forename: Emma
authors.initials: E
authors.lastname: Nye
authors.forename: Gordon
authors.initials: G
authors.lastname: Stamp
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
authors.forename: Julian
authors.initials: J
authors.lastname: Downward
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002417:Cattle; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D058534:Class I Phosphatidylinositol 3-Kinases; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D044148:Lymphatic Abnormalities / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D017354:Point Mutation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D015398:Signal Transduction; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D036341:Intercellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; C509622:1-phosphatidylinositol 3-kinase p110 subunit, mouse; C495971:Hras protein, mouse