Hippo Reprograms the Transcriptional Response to Ras Signaling

Publication date: 25 September 2017
Source:Developmental Cell, Volume 42, Issue 6
Author(s): Justine Pascual, Jelle Jacobs, Leticia Sansores-Garcia, Malini Natarajan, Julia Zeitlinger, Stein Aerts, Georg Halder, Fisun Hamaratoglu
Hyperactivating mutations in Ras signaling are hallmarks of carcinomas. Ras signaling mediates cell fate decisions as well as proliferation during development. It is not known what dictates whether Ras signaling drives differentiation versus proliferation. Here we show that the Hippo pathway is critical for this decision. Loss of Hippo switches Ras activation from promoting cellular differentiation to aggressive cellular proliferation. Transcriptome analysis combined with genetic tests show that this excessive proliferation depends on the synergistic induction of Ras target genes. Using ChIP-nexus, we find that Hippo signaling keeps Ras targets in check by directly regulating the expression of two key downstream transcription factors of Ras signaling: the ETS-domain transcription factor Pointed and the 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.

Teaser

How is the cellular response to Ras activation—differentiation versus proliferation—determined? Pascual et al. show that the Hippo pathway helps decide by controlling expression of Ras effector genes, including the repressor Capicua. Capicua acts with Hippo signaling to repress and restrict the expression of a gene subset to prevent hyperproliferation.


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