EGFR signaling activates intestinal stem cells by promoting mitochondrial biogenesis and β-oxidation

EGFR-RAS-ERK signaling promotes growth and proliferation in many cell types, and genetic hyperactivation of RAS-ERK signaling drives many cancers. Yet, despite intensive study of upstream components in EGFR signal transduction, the identities and functions of downstream effectors in the pathway are poorly understood. In Drosophila intestinal stem cells (ISCs), the transcriptional repressor Capicua (Cic) and its targets, the ETS-type transcriptional activators Pointed (pnt) and Ets21C, are essential downstream effectors of mitogenic EGFR signaling. Here, we show that these factors promote EGFR-dependent metabolic changes that increase ISC mass, mitochondrial growth, and mitochondrial activity. Gene target analysis using RNA and DamID sequencing revealed that Pnt and Ets21C directly upregulate not only DNA replication and cell cycle genes but also genes for oxidative phosphorylation, the TCA cycle, and fatty acid beta-oxidation. Metabolite analysis substantiated these metabolic functions. The mitochondrial transcription factor B2 (mtTFB2), a direct target of Pnt, was required and partially sufficient for EGFR-driven ISC growth, mitochondrial biogenesis, and proliferation. MEK-dependent EGF signaling stimulated mitochondrial biogenesis in human RPE-1 cells, indicating the conservation of these metabolic effects. This work illustrates how EGFR signaling alters metabolism to coordinately activate cell growth and cell division.

Automated summary

This study reveals that the transcriptional repressor Cic and its targets, pnt and Ets21C, are downstream effectors of mitogenic EGFR signaling in Drosophila intestinal stem cells. These factors promote metabolic changes that increase ISC mass, mitochondrial growth, and activity. The study also shows that Pnt and Ets21C directly upregulate genes involved in DNA replication, cell cycle, oxidative phosphorylation, TCA cycle, and fatty acid beta-oxidation. The work highlights the role of EGFR signaling in coordinating cell growth and division through alterations in metabolism.