Hippo reprograms the transcriptional response to Ras signalling

Mutations that lead to hyperactivation of Ras signaling are hallmarks of carcinomas. During development, signaling via Ras mediates cell fate decisions and cellular differentiation without causing hyper-proliferation. What determines whether Ras activation leads to differentiation or proliferation remains unknown. Here we show that the Hippo pathway reprograms the cellular response to Ras signaling in Drosophila. While hyperactivation of Ras signaling alone promotes cellular differentiation, additional loss of Hippo signaling drives aggressive hyper-proliferation. Transcriptome analysis combined with ChIP-nexus confirmed that the magnitude and specificity of Ras target gene expression strongly depends on the activity status of the Hippo pathway. This is because Hippo signaling directly regulates the expression of two key downstream transcription factors of the Ras pathway: the ETS-domain transcription factor Pointed and the transcriptional repressor Capicua. Our results highlight how independent signaling pathways can impinge on each other at the level of transcription factors, thereby providing a safety mechanism to keep proliferation in check under normal developmental conditions.? Overall design: RNA-seq on ?wing imaginal discs? from 3rd instar Drosophila larvae with wild type control, cic or wts single mutant and cic wts double-mutant cell clones. ChIP-Nexus-seq against Scalloped and Capicua on wing imaginal discs? from 3rd instar Drosophila larvae with wild type control, wts single mutant and cic wts double-mutant cell clones.