RAL GTPases mediate EGFR-driven intestinal stem cell proliferation and tumourigenesis

Elife. 2021 Jun 7:10:e63807. doi: 10.7554/eLife.63807.

Abstract

RAS-like (RAL) GTPases function in Wnt signalling-dependent intestinal stem cell proliferation and regeneration. Whether RAL proteins work as canonical RAS effectors in the intestine and the mechanisms of how they contribute to tumourigenesis remain unclear. Here, we show that RAL GTPases are necessary and sufficient to activate EGFR/MAPK signalling in the intestine, via induction of EGFR internalisation. Knocking down Drosophila RalA from intestinal stem and progenitor cells leads to increased levels of plasma membrane-associated EGFR and decreased MAPK pathway activation. Importantly, in addition to influencing stem cell proliferation during damage-induced intestinal regeneration, this role of RAL GTPases impacts on EGFR-dependent tumourigenic growth in the intestine and in human mammary epithelium. However, the effect of oncogenic RAS in the intestine is independent from RAL function. Altogether, our results reveal previously unrecognised cellular and molecular contexts where RAL GTPases become essential mediators of adult tissue homeostasis and malignant transformation.

Keywords: D. melanogaster; EGFR signalling; cancer biology; drosophila; human; intestinal regeneration; mouse; ral proteins; regenerative medicine; stem cells; tumourigenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Breast Neoplasms / enzymology
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Proliferation*
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism*
  • Cell Transformation, Neoplastic / pathology
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster / enzymology*
  • Drosophila melanogaster / genetics
  • Endocytosis
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism*
  • Female
  • Humans
  • Hyperplasia
  • Intestinal Mucosa / metabolism*
  • Intestinal Mucosa / pathology
  • Lung Neoplasms / enzymology
  • Lung Neoplasms / genetics
  • Lung Neoplasms / pathology
  • Mammary Glands, Human / enzymology
  • Mammary Glands, Human / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mitogen-Activated Protein Kinases / metabolism
  • Monomeric GTP-Binding Proteins / genetics
  • Monomeric GTP-Binding Proteins / metabolism*
  • Receptors, Invertebrate Peptide / genetics
  • Receptors, Invertebrate Peptide / metabolism*
  • Signal Transduction
  • Stem Cells / metabolism*
  • Stem Cells / pathology
  • ral GTP-Binding Proteins / genetics
  • ral GTP-Binding Proteins / metabolism*

Substances

  • Drosophila Proteins
  • Receptors, Invertebrate Peptide
  • EGFR protein, human
  • Egfr protein, Drosophila
  • ErbB Receptors
  • Mitogen-Activated Protein Kinases
  • RALA protein, human
  • Monomeric GTP-Binding Proteins
  • RalA protein, Drosophila
  • ral GTP-Binding Proteins

Associated data

  • GEO/GSE162421