E-cadherin-mediated adhesion inhibits ligand-dependent activation of diverse receptor tyrosine kinases

EMBO J. 2004 Apr 21;23(8):1739-48. doi: 10.1038/sj.emboj.7600136. Epub 2004 Apr 1.

Abstract

E-cadherin is an essential adhesion protein as well as a tumor suppressor that is silenced in many cancers. Its adhesion-dependent regulation of signaling has not been elucidated. We report that E-cadherin can negatively regulate, in an adhesion-dependent manner, the ligand-dependent activation of divergent classes of receptor tyrosine kinases (RTKs), by inhibiting their ligand-dependent activation in association with decreases in receptor mobility and in ligand-binding affinity. E-cadherin did not regulate a constitutively active mutant RTK (Neu*) or the ligand-dependent activation of LPA receptors or muscarinic receptors, which are two classes of G protein-coupled receptors. EGFR regulation by E-cadherin was associated with complex formation between EGFR and E-cadherin that depended on the extracellular domain of E-cadherin but was independent of beta-catenin binding or p120-catenin binding. Transfection of E-cadherin conferred negative RTK regulation to human melanoma and breast cancer lines with downregulated endogenous E-cadherin. Abrogation of E-cadherin regulation may contribute to the frequent ligand-dependent activation of RTK in tumors.

MeSH terms

  • Animals
  • Cadherins / genetics
  • Cadherins / metabolism*
  • Catenins
  • Cell Adhesion / drug effects
  • Cell Adhesion Molecules / genetics
  • Cell Adhesion Molecules / metabolism
  • Cell Line
  • Cell Membrane / metabolism
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism
  • DNA / biosynthesis
  • Dogs
  • Enzyme Activation
  • Epidermal Growth Factor / pharmacology
  • Epithelial Cells / cytology
  • Epithelial Cells / metabolism
  • ErbB Receptors / metabolism*
  • Humans
  • Ligands
  • Mutation / genetics
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Protein Transport
  • Receptor, ErbB-2 / genetics
  • Receptor, ErbB-2 / metabolism*
  • Receptor, IGF Type 1 / metabolism*
  • Receptors, G-Protein-Coupled / metabolism
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Transformation, Genetic / genetics
  • beta Catenin

Substances

  • CTNNB1 protein, human
  • Cadherins
  • Catenins
  • Cell Adhesion Molecules
  • Cytoskeletal Proteins
  • Ligands
  • Phosphoproteins
  • Receptors, G-Protein-Coupled
  • Trans-Activators
  • beta Catenin
  • delta catenin
  • Epidermal Growth Factor
  • DNA
  • ErbB Receptors
  • Receptor, ErbB-2
  • Receptor, IGF Type 1