Abstract
The small G-protein Ras is a conserved regulator of cell and tissue growth. These effects of Ras are mediated largely through activation of a canonical RAF-MEK-ERK kinase cascade. An important challenge is to identify how this Ras/ERK pathway alters cellular metabolism to drive growth. Here we report on stimulation of RNA polymerase III (Pol III)-mediated tRNA synthesis as a growth effector of Ras/ERK signalling in Drosophila. We find that activation of Ras/ERK signalling promotes tRNA synthesis both in vivo and in cultured Drosophila S2 cells. We also show that Pol III function is required for Ras/ERK signalling to drive proliferation in both epithelial and stem cells in Drosophila tissues. We find that the transcription factor Myc is required but not sufficient for Ras-mediated stimulation of tRNA synthesis. Instead we show that Ras signalling promotes Pol III function and tRNA synthesis by phosphorylating, and inhibiting the nuclear localization and function of the Pol III repressor Maf1. We propose that inhibition of Maf1 and stimulation of tRNA synthesis is one way by which Ras signalling enhances protein synthesis to promote cell and tissue growth.
Highlights
The Ras small G-protein is one of the key conserved regulators of cell growth and proliferation
We identify the stimulation of tRNA synthesis as an important mechanism by which Ras functions
We show that Ras promotes tRNA synthesis by inhibiting Maf1, a protein that normally inhibits RNA polymerase III, the enzyme complex that stimulates tRNA synthesis
Summary
The Ras small G-protein is one of the key conserved regulators of cell growth and proliferation. Over three decades of research have defined the textbook model of how Ras is activated by growth factors to stimulate a core RAF kinase, MEK (Mitogen-activated protein kinase kinase) and ERK (Extracellular signal–regulated kinase) signalling cascade. Work in model organisms such as Drosophila, C elegans and mouse has shown how this Ras/ERK pathway coordinates tissue growth and patterning to control organ size during development and homeostatic growth in adults. Most notably, activating mutations in Ras and RAF occur in a large percentage of cancers, and lead to hyper-activation of ERK, which drives tumour formation in both epithelial and stem cells [1]. Understanding how Ras promotes cell proliferation and tissue growth is an important concern in biology
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