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Regulation of cadherin-mediated adhesion in morphogenesis

Key Points

  • This article considers how the dynamic regulation of cadherin-mediated adhesion at the cell surface controls tissue morphogenesis.

  • The cadherins make up a large superfamily of adhesion proteins, which includes the classic cadherins, the desmosomal cadherins, the protocadherins and the cadherin-like signalling receptors. The classic cadherins, which interact with catenins and form adherens junctions, are the focus of this review.

  • Cadherin cell adhesion proteins mediate many facets of tissue morphogenesis. Dynamic regulation of cadherins in response to different extracellular signals controls cell sorting, cell rearrangements and cell movements.

  • Cadherins may be regulated at the cell surface by an inside-out signalling mechanism analogous to the integrins. The structure of the cadherin homophilic bond and the changes in the bond responsible for regulation is incompletely understood, but biophysical and crystallographic studies have led to several different models for the structure of the homophilic bond.

  • Classic cadherins are intimately associated with the actin cytoskeleton, especially at the adherens junctions. Attachment to the actin cytoskeleton and the formation of adherens junctions are probably not essential for the formation of the basic adhesive bond itself. However, coupling the actin cytoskeleton to sites of adhesion is needed for morphogenesis because it produces force and helps to organize cell structure; it can generate changes in cell shape, drive cell movements and establish cell polarity.

  • The catenins (α-catenin, β-catenin and p120-catenin) have at least three distinct roles in cadherin function; they mediate a direct physical link to the actin cytoskeleton, they interact with signalling molecules that regulate the actin cytoskeleton, and they directly control the adhesive state of the cadherin extracellular binding domain.

  • Several kinds of signalling pathways have been found to regulate cadherin-mediated adhesion. Many receptor tyrosine kinases negatively regulate adhesion, whereas the small GTPases of both the Rho family and the Ras family have many different affects on adhesion. Tyrosine phosphorylation of β-catenin and p120 are frequently observed, and one hypothesis is that this phosphorylation regulates the structure of the catenins and cadherin cytoplasmic domain to control the state of the extracellular homophilic binding domain.

Abstract

Cadherin cell-adhesion proteins mediate many facets of tissue morphogenesis. The dynamic regulation of cadherins in response to various extracellular signals controls cell sorting, cell rearrangements and cell movements. Cadherins are regulated at the cell surface by an inside-out signalling mechanism that is analogous to the integrins in platelets and leukocytes. Signal-transduction pathways impinge on the catenins (cytoplasmic cadherin-associated proteins), which transduce changes across the membrane to alter the state of the cadherin adhesive bond.

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Figure 1: Cadherin regulation in tissue morphogenesis
Figure 2: The adherens junction and the classic cadherin–catenin complex.
Figure 3: Various models of the cadherin homophilic bond.
Figure 4: Three ways in which catenins contribute to cadherin function.

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Acknowledgements

I thank members of my laboratory, D. Desimone and J. White for valuable discussions and comments. B.M.G. is supported by grants from the National Institutes of Health.

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DATABASES

Swiss-Port

E-cadherin

Cdc42

FAT

vinculin

ZO1

Prosite

cadherins

Glossary

ADHERENS JUNCTION

Close cell–cell contacts that are observed by electron microscopy and that are often associated with actin filaments at the cytoplasmic surface.

GROWTH CONE

Motile tip of the axon or dendrite of a growing nerve cell, which spreads out into a large cone-shaped appendage.

HOMOPHILIC BINDING

The binding of a molecule (for example, an adhesion molecule) in one cell to an identical molecule that is usually on another cell.

WNT

A family of highly conserved, secreted signalling molecules that regulate inductive interactions during embryogenesis as well as stem cell growth in adult tissues.

FIBRONECTIN

An extracellular-matrix protein that functions to support strong cell adhesion and motility through the cell-surface receptor integrin α5β1 — an adhesion receptor that also causes intracellular signalling.

INTEGRINS

A large family of heterodimeric transmembrane proteins that function as receptors for cell-adhesion molecules.

IMAGINAL DISC

A single-cell-layer epithelial structure of the Drosophila melanogaster larva that gives rise to wings, legs and other appendages.

HEDGEHOG

A family of secreted signalling molecules that mediates inductive interactions in embryos.

RHOMBOMERE

Neuroepithelial segments that are found transiently in the embryonic hindbrain and that adopt distinct molecular and cellular properties, restrictions in cell mixing, and ordered domains of gene expression.

BORDER CELLS

Four to eight epithelial follicle cells in the developing Drosophila melanogaster ovary. These cells are recruited by two non-migratory polar cells and migrate towards the anterior border of the oocyte.

CIS DIMER

A dimer on the same membrane. A trans dimer is a dimer on the facing membrane.

ALLOSTERIC SWITCHES

Switches that function by causing a conformational change in a protein.

GPI-LINKED

A post-translational modification that attaches proteins to the exoplasmic leaflet of membranes by a lipid moiety.

FORMIN PROTEINS

A family of proteins that contain a formin homology-2 domain and that can promote actin assembly.

SMALL GTPASES

GDP/GTP-regulated binary switches that regulate signal-transduction. The GDP-bound form of the GTPase is usually inactive, whereas the GTP-bound form is active and activates downstream signalling pathways that control actin organization.

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Gumbiner, B. Regulation of cadherin-mediated adhesion in morphogenesis. Nat Rev Mol Cell Biol 6, 622–634 (2005). https://doi.org/10.1038/nrm1699

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