E-cadherin-mediated adhesion inhibits ligand-dependent activation of diverse receptor tyrosine kinases.
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.
Qian
Xiaolan
X
Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
Karpova
Tatiana
T
Sheppard
Allan M
AM
McNally
James
J
Lowy
Douglas R
DR
D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D051177:Catenins; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D004285:Dogs; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D009154:Mutation / Q000235:genetics; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014170:Transformation, Genetic / Q000235:genetics; D051176:beta Catenin; D000095002:Delta Catenin
D015820:Cadherins; D051177:Catenins; D015815:Cell Adhesion Molecules; D003598:Cytoskeletal Proteins; D004247:DNA; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D008024:Ligands; D010750:Phosphoproteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D017526:Receptor, IGF Type 1; D043562:Receptors, G-Protein-Coupled; D015534:Trans-Activators; D051176:beta Catenin; D000095002:Delta Catenin; C495270:CTNNB1 protein, human