The major β-catenin/E-cadherin junctional binding site is a primary molecular mechano-transductor of differentiation in vivo

ELife
Jens-Christian RöperEmmanuel Farge

Abstract

In vivo, the primary molecular mechanotransductive events mechanically initiating cell differentiation remain unknown. Here we find the molecular stretching of the highly conserved Y654-β-catenin-D665-E-cadherin binding site as mechanically induced by tissue strain. It triggers the increase of accessibility of the Y654 site, target of the Src42A kinase phosphorylation leading to irreversible unbinding. Molecular dynamics simulations of the β-catenin/E-cadherin complex under a force mimicking a 6 pN physiological mechanical strain predict a local 45% stretching between the two α-helices linked by the site and a 15% increase in accessibility of the phosphorylation site. Both are quantitatively observed using FRET lifetime imaging and non-phospho Y654 specific antibody labelling, in response to the mechanical strains developed by endogenous and magnetically mimicked early mesoderm invagination of gastrulating Drosophila embryos. This is followed by the predicted release of 16% of β-catenin from junctions, observed in FRAP, which initiates the mechanical activation of the β-catenin pathway process.

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Citations

Jan 10, 2020·Wiley Interdisciplinary Reviews. Systems Biology and Medicine·Jia GouHans G Othmer
May 16, 2020·Biochemical Society Transactions·Pablo Astudillo
Jun 15, 2019·International Journal of Molecular Sciences·Amanda C DaulagalaAntonis Kourtidis
Jul 23, 2019·F1000Research·Willem-Jan PannekoekMartijn Gloerich
Oct 31, 2020·Biofabrication·Jose E PerezClaire Wilhelm
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Feb 16, 2021·Developmental Biology·Iain Martyn, Zev J Gartner
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Jun 10, 2021·Developmental Cell·Mary-Kate HaywardValerie M Weaver
May 18, 2021·Molecular and Cellular Biochemistry·Malak El SabehMostafa A Borahay
Sep 14, 2021·Blood Advances·Rosa A Krimpenfort, Micha Nethe
Jul 5, 2021·Current Opinion in Cell Biology·Vinay Swaminathan, Martijn Gloerich
Dec 23, 2020·Developmental Cell·Clayton Schwarz, Anna-Katerina Hadjantonakis
Jan 13, 2022·Journal of Cellular and Molecular Medicine·Joanna K LedwonJolanta M Topczewska

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Datasets Mentioned

BETA
BAA05942.1
AAK92991.1

Methods Mentioned

BETA
fluorescence
FRET
Immunoprecipitation

Software Mentioned

SwissModel
Modloop
NAMD
Fortran
SymphoTime
Packing Analyzer
CHARMM36
DE
BLAST
Rstudio

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