Feedback regulation through myosin II confers robustness on RhoA signalling at E-cadherin junctions

Nat Cell Biol. 2015 Oct;17(10):1282-93. doi: 10.1038/ncb3239. Epub 2015 Sep 14.

Abstract

Actomyosin at the epithelial zonula adherens (ZA) generates junctional tension for tissue integrity and morphogenesis. This requires the RhoA GTPase, which establishes a strikingly stable active zone at the ZA. Mechanisms must then exist to confer robustness on junctional RhoA signalling at the population level. We now identify a feedback network that generates a stable mesoscopic RhoA zone out of dynamic elements. The key is scaffolding of ROCK1 to the ZA by myosin II. ROCK1 protects junctional RhoA by phosphorylating Rnd3 to prevent the cortical recruitment of the Rho suppressor, p190B RhoGAP. Combining predictive modelling and experimentation, we show that this network constitutes a bistable dynamical system that is realized at the population level of the ZA. Thus, stability of the RhoA zone is an emergent consequence of the network of interactions that allow myosin II to feedback to RhoA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adherens Junctions / metabolism*
  • Animals
  • Caco-2 Cells
  • Cadherins / genetics
  • Cadherins / metabolism*
  • Dogs
  • Feedback, Physiological
  • Fluorescence Resonance Energy Transfer
  • GTPase-Activating Proteins / genetics
  • GTPase-Activating Proteins / metabolism
  • HEK293 Cells
  • Humans
  • Immunoblotting
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • MCF-7 Cells
  • Madin Darby Canine Kidney Cells
  • Microscopy, Confocal
  • Microscopy, Fluorescence
  • Myosin Type II / genetics
  • Myosin Type II / metabolism*
  • Phosphorylation
  • RNA Interference
  • Signal Transduction*
  • rho GTP-Binding Proteins / genetics
  • rho GTP-Binding Proteins / metabolism
  • rho-Associated Kinases / genetics
  • rho-Associated Kinases / metabolism
  • rhoA GTP-Binding Protein / genetics
  • rhoA GTP-Binding Protein / metabolism*

Substances

  • ARHGAP5 protein, human
  • Cadherins
  • GTPase-Activating Proteins
  • Luminescent Proteins
  • ROCK1 protein, human
  • rho-Associated Kinases
  • Myosin Type II
  • RND3 protein, human
  • rho GTP-Binding Proteins
  • rhoA GTP-Binding Protein