Binding of Ras to Phosphoinositide 3-Kinase p110α 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.

Oncogenic signaling of class I PI3K isoforms

“…recently been shown to be essential (Gupta et al, 2007). Here we characterize the nature of the requirement for Ras by showing that constitutively membrane-localized p110g and p110b do not require an interaction with Ras for full oncogenic activity.…”

Loss of PI3K blocks cell-cycle progression in a Drosophila tumor model

“…Discs were stained for Fasciclin 3 to visualize disc outlines (blue) and for PH3 to mark cells in M-phase ((a-f) in red and (a 00 -e 00 ) and (f 0 ) in gray). PI3K signaling is low in Ras V12 , Dlg RNAi tumors From mammalian systems, it is known that Ras binds to PI3K and that oncogenic transformation in response to Ras depends on PI3K activity (Rodriguez-Viciana et al, 1994, 1997Gupta et al, 2007). In Drosophila, it was shown that PI3K is not required for physiological Ras signaling (Halfar et al, 2001;Prober and Edgar, 2002).…”

Visualization of Ras-PI3K interaction in the endosome using BiFC

“…On the other hand, a recent studies using knock-in mice where the RBD of PI3K is substituted with a mutant RBD that is unable to bind Ras has shown that Ras-PI3K binding is essential for a variety of pathophysiological events, including the development of the lymphatic vasculature [42]. In endothelial cell lineages, the Ras-PI3K pathway and the internalization of vascular endothelial growth factor (VEGF) receptor 1 are involved in VEGF-dependent endothelial cell motility [43] and angiogenesis [44].…”

“…In endothelial cell lineages, the Ras-PI3K pathway and the internalization of vascular endothelial growth factor (VEGF) receptor 1 are involved in VEGF-dependent endothelial cell motility [43] and angiogenesis [44]. It is thus possible that a defect in the endocytosis of receptors such as VEGF receptor 3 in lymphatic endothelial cells is the cause of the impaired lymphatic development in PI3K mutant mice [42], considering the crucial role for Ras-PI3K signaling in local PIP 3 production in the endosome, as shown by this study (Fig. 5a-d and g).…”