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

Chenge Zhang1, Yinhua Jin2, Marco Marchetti1

  • 1Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA; Center for Molecular Biology, Heidelberg University (ZMBH) & German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.

Current Biology : CB
|July 27, 2022
PubMed

Insights

Epidermal growth factor receptor (EGFR) signaling activates cell growth and division by reprogramming cell metabolism. Downstream factors like Pointed (Pnt) and Ets21C regulate mitochondrial activity and gene expression, promoting proliferation.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Metabolic Regulation

Background:

  • Epidermal growth factor receptor (EGFR) signaling is crucial for cell growth and proliferation.
  • Dysregulation of RAS-ERK signaling, downstream of EGFR, is implicated in cancer.
  • Downstream effectors of EGFR signaling, particularly in stem cells, remain incompletely understood.

Purpose of the Study:

  • To identify and characterize downstream effectors of EGFR signaling in Drosophila intestinal stem cells (ISCs).
  • To investigate the role of these effectors in regulating cell metabolism and proliferation.
  • To determine the conservation of these mechanisms in human cells.

Main Methods:

  • Drosophila intestinal stem cell (ISC) culture and genetic manipulation.
  • RNA sequencing and DamID sequencing for gene target analysis.
  • Metabolite analysis and mitochondrial activity assays.
  • Functional studies using gene knockdown and overexpression, including mtTFB2.
  • Experiments in human RPE-1 cells to assess conserved mechanisms.

Main Results:

  • Capicua (Cic), Pointed (Pnt), and Ets21C are essential downstream effectors of EGFR signaling in ISCs.
  • Pnt and Ets21C directly upregulate genes involved in DNA replication, cell cycle, oxidative phosphorylation, TCA cycle, and fatty acid beta-oxidation.
  • EGFR signaling promotes ISC mass, mitochondrial growth, and activity via these transcriptional targets.
  • The mitochondrial transcription factor B2 (mtTFB2) is a direct Pnt target required for EGFR-driven ISC growth and proliferation.
  • MEK-dependent EGF signaling stimulates mitochondrial biogenesis in human RPE-1 cells, indicating conserved metabolic effects.

Conclusions:

  • EGFR signaling coordinates cell growth and division by altering cellular metabolism through downstream effectors like Pnt and Ets21C.
  • These factors regulate mitochondrial biogenesis and activity, essential for stem cell proliferation.
  • The identified EGFR-METABOLISM axis is conserved across species, highlighting its fundamental role in cell growth regulation.
Keywords:
Ets21CISCPointedintestinal stem cellmitochondrial biogenesismtTFB2proliferation

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