Binding of ras to phosphoinositide 3-kinase p110alpha is required for ras-driven tumorigenesis in mice.
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.
Gupta
Surbhi
S
Signal Transduction Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
Ramjaun
Antoine R
AR
Haiko
Paula
P
Wang
Yihua
Y
Warne
Patricia H
PH
Nicke
Barbara
B
Nye
Emma
E
Stamp
Gordon
G
Alitalo
Kari
K
Downward
Julian
J
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*
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