Binding of ras to phosphoinositide 3-kinase p110alpha is required for ras-driven tumorigenesis in mice
Surbhi Gupta1, Antoine R Ramjaun, Paula Haiko
1Signal Transduction Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
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.
Insights
Ras protein interaction with phosphoinositide 3-kinase (PI3K) is vital for normal cell growth and Ras-driven tumor formation in vivo. Blocking this interaction in mice prevents tumor development and impacts lymphatic vasculature growth.
Area of Science:
- Molecular Biology
- Cellular Signaling
- Oncology
Background:
- Ras proteins are key regulators of cell signaling, interacting with effector enzymes like phosphoinositide 3-kinases (PI3Ks).
- Previous studies established Ras-PI3K interaction in cell cultures, but in vivo evidence for its role in normal and malignant growth was lacking.
Purpose of the Study:
- To investigate the in vivo role of the interaction between endogenous Ras and the p110alpha isoform of PI3K in normal cell growth and oncogenesis.
- To determine the necessity of this interaction for Ras-driven tumor formation.
Main Methods:
- Generation of mice with mutations in the Pi3kca gene, specifically blocking the interaction between Ras and the p110alpha catalytic subunit.
- Analysis of cellular proliferation, growth factor signaling pathways, and lymphatic vasculature development in mutant mice.
- Assessment of tumor development in response to endogenous Ras oncogenes.
Main Results:
- Cells from mutant mice exhibited proliferative defects and disrupted growth factor signaling to PI3K.
- Mutant mice displayed defective lymphatic vasculature development, leading to perinatal chylous ascites.
- Mice were highly resistant to Ras oncogene-induced tumorigenesis.
Conclusions:
- The interaction of Ras with p110alpha is essential in vivo for specific normal growth factor signaling pathways.
- This Ras-p110alpha interaction is critically required for Ras-driven tumor formation, highlighting it as a potential therapeutic target.
