EGFR Signaling Activates Intestinal Stem Cells By​ Promoting Mitochondrial Biogenesis

Abstract

EGFR-RAS-ERK signaling promotes growth and proliferation in many cell types, and genetic hyperactivation of RAS-ERK signaling is a common driver in many cancers. Yet despite intensive study of upstream components in EGFR signal transduction, the identities and functions of downstream effectors in the pathway are largely unknown. Knowledge of these effector mechanisms will provide novel routes for the treatment of diseases of dysregulated cell growth, notably cancer. In Drosophila intestinal stem cells (ISC) the transcriptional repressor Capicua (cic) and its targets, the ETS-type transcriptional activators Pointed (pnt) and Ets21C, are essential effectors of mitogenic EGFR signaling. Here we show that Pnt and Ets21C promote EGFR-dependent metabolic changes that increase ISC mass, mitochondrial growth, and mitochondrial activity. Gene target analysis using RNA- and DamID-sequencing revealed that these ETS factors directly up-regulate not only DNA replication and cell cycle genes, but also genes used for oxidative phosphorylation, the TCA cycle, and fatty acid oxidation. Metabolic profiling showed that EGFR signaling depleted glycolytic intermediates and lipids, indicating increased glycolysis and fatty acid beta-oxidation. We found that mitochondrial transcription factor B2 (mtTFB2), a direct target of Pnt, was required and even sufficient for EGFR-driven ISC growth, mitochondrial biogenesis and cell proliferation. Notably, MEK-dependent EGF signaling also stimulated mitochondrial biogenesis in human RPE-1 cells, indicating conservation of these metabolic effects. This work illustrates how EGFR signaling alters metabolism to coordinately activate cell growth and cell division.