P120 catenin potentiates constitutive E-cadherin dimerization at the plasma membrane and regulates trans binding

Vinh Vu, Taylor Light, Brendan Sullivan, Diana Greiner, Kalina Hristova, Deborah Leckband

Research output: Contribution to journalArticlepeer-review


Cadherins are essential adhesion proteins that regulate tissue cohesion and paracellular permeability by assembling dense adhesion plaques at cell-to-cell contacts. Adherens junctions are central to a wide range of tissue functions; identifying protein interactions that potentiate their assembly and regulation has been the focus of research for over 2 decades. Here, we present evidence for a new, unexpected mechanism of cadherin oligomerization on cells. Fully quantified spectral imaging fluorescence resonance energy transfer (FSI-FRET) and fluorescence intensity fluctuation (FIF) measurements directly demonstrate that E-cadherin forms constitutive lateral (cis) dimers at the plasma membrane. Results further show that binding of the cytosolic protein p120ctn binding to the intracellular region is required for constitutive E-cadherin dimerization. This finding differs from a model that attributes lateral (cis) cadherin oligomerization solely to extracellular domain interactions. The present, novel findings are further supported by studies of E-cadherin mutants that uncouple p120ctn binding or with cells in which p120ctn was knocked out using CRISPR-Cas9. Quantitative affinity measurements further demonstrate that uncoupling p120ctn binding reduces the cadherin trans binding affinity and cell adhesion. These findings transform the current model of cadherin assembly at cell surfaces and identify the core building blocks of cadherin-mediated intercellular adhesions. They also identify a new role for p120ctn and reconcile findings that implicate both the extracellular and intracellular cadherin domains in cadherin clustering and intercellular cohesion.

Original languageEnglish (US)
Pages (from-to)3017-3027.e7
JournalCurrent Biology
Issue number14
StatePublished - Jul 26 2021


  • FIF
  • FRET
  • cadherin
  • cis dimers
  • fluorescence intensity fluctuations
  • fluorescence resonance energy transfer
  • inside-out signaling
  • oligomerization
  • p120 catenin

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology
  • General Agricultural and Biological Sciences


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