Interactions between Ras1, dMyc, and dPI3K signaling in the developing Drosophila wing

Abstract

The Ras GTPase links extracellular signals to intracellular mechanisms that control cell growth, the cell cycle, and cell identity. An activated form of Drosophila Ras (Ras V12 ) promotes these processes in the developing wing, but the effector pathways involved are unclear. Here, we present evidence indicating that Ras V12 promotes cell growth and G 1 /S progression by increasing dMyc protein levels and activating dPI3K signaling, and that it does so via separate effector pathways. We also show that endogenous Ras is required to maintain normal levels of dMyc, but not dPI3K signaling during wing development. Finally, we show that induction of dMyc and regulation of cell identity are separable effects of Raf/MAPK signaling. These results suggest that Ras may only affect PI3K signaling when mutationally activated, such as in Ras V12 -transformed cells, and provide a basis for understanding the synergy between Ras and other growth-promoting oncogenes in cancer.

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

“…In agreement with previous reports, we find that Ras V12 induces the PI3K pathway in Drosophila (Prober and Edgar, 2002). Yet curiously, Ras V12 , Dlg RNAi tumors exhibit low levels of PI3K signaling.…”

“…This interpretation implies that the activation of PI3K through Ras V12 depends on proper cell polarity. In support of this explanation, Prober and Edgar (2002) reported that Ras V12 activates the PIP 3 reporter only at the apical side of cells. Additionally, studies have shown that PTEN directly binds to the polarity gene Bazooka and that the activity of the PI3K pathway is polarized in Drosophila oocyte cells (von Stein et al, 2005).…”

“…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). However, PI3K activity, monitored by a PIP 3 reporter, was increased in cells expressing oncogenic Ras V12 (Prober and Edgar, 2002), indicating that abnormally high levels of Ras activity can lead to PI3K activation in Drosophila.…”

“…In Drosophila, it was shown that PI3K is not required for physiological Ras signaling (Halfar et al, 2001;Prober and Edgar, 2002). However, PI3K activity, monitored by a PIP 3 reporter, was increased in cells expressing oncogenic Ras V12 (Prober and Edgar, 2002), indicating that abnormally high levels of Ras activity can lead to PI3K activation in Drosophila. We studied PI3K signaling levels in the Ras V12 , Dlg RNAi tumor assay to test for a possible correlation between PI3K signaling levels and PI3K sensitivity.…”

Myc in model organisms: A view from the flyroom

“…Interestingly, many of the Minute genes, as part of the large number of genes involved in ribosomal biogenesis, are dMyc transcriptional targets. Also, as mentioned above, dMyc expression is influenced by Wg and Dpp [19,21,51]. These observations might imply that all cell competition -competition involving dMyc, a reduction in ribosome biogenesis, or lack of patterning factors -operates by the same mechanism.…”