Plasma membrane proteoglycans syndecan-2 and syndecan-4 engage with EGFR and RON kinase to sustain carcinoma cell cycle progression

J Biol Chem. 2022 Jun;298(6):102029. doi: 10.1016/j.jbc.2022.102029. Epub 2022 May 13.

Abstract

Epidermal growth factor receptor (EGFR) is a causal factor in carcinoma, yet many carcinoma patients are resistant to EGFR inhibitors. Potential insight into this resistance stems from prior work that showed EGFR in normal epithelial cells docks to the extracellular domain of the plasma membrane proteoglycan syndecan-4 (Sdc4) engaged with α3β1 and α6β4 integrins. We now report that this receptor complex is modified by the recruitment of syndecan-2 (Sdc2), the Recepteur d'Origine Nantais (RON) tyrosine kinase, and the cellular signaling mediator Abelson murine leukemia viral oncogene homolog 1 (ABL1) in triple-negative breast carcinoma and head and neck squamous cell carcinoma, where it contributes to EGFR kinase-independent proliferation. Treatment with a peptide mimetic of the EGFR docking site in the extracellular domain of Sdc4 (called SSTNEGFR) disrupts the entire complex and causes a rapid, global arrest of the cell cycle. Normal epithelial cells do not recruit these additional receptors to the adhesion mechanism and are not arrested by SSTNEGFR. Although EGFR docking with Sdc4 in the tumor cells is required, cell cycle progression does not depend on EGFR kinase. Instead, progression depends on RON kinase, activated by its incorporation into the complex. RON activates ABL1, which suppresses p38 mitogen-activated protein kinase and prevents a p38-mediated signal that would otherwise arrest the cell cycle. These findings add to the growing list of receptor tyrosine kinases that support tumorigenesis when activated by their association with syndecans at sites of matrix adhesion and identify new potential targets for cancer therapy.

Keywords: Abl tyrosine kinase; Recepteur d’Origine Nantais (RON); breast cancer; cell cycle; epidermal growth factor receptor (EGFR); head and neck cancer; integrin; macrophage stimulating receptor (MST1R); p38MAPK; syndecan.

MeSH terms

  • Animals
  • Carcinoma*
  • Cell Cycle
  • Cell Membrane / metabolism
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Glucans
  • Humans
  • Mice
  • Syndecan-2 / genetics
  • Syndecan-4* / chemistry

Substances

  • Glucans
  • Syndecan-4
  • rice bran saccharide
  • Syndecan-2
  • EGFR protein, human
  • ErbB Receptors