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Rho-family GTPases in cadherin-mediated cell — cell adhesion

Nature Reviews Molecular Cell Biology volume 2, pages 887–897 (2001)Cite this article

Key Points

  • Cell?cell adhesions are rearranged dynamically during a wide range of physiological processes, such as tissue development and tumour metastasis.

  • Cadherins are an important group of cell?cell adhesion molecules that mediate adhesion by Ca2+-dependent homophilic interactions.

  • Recently, Rho-family GTPases, including RhoA, Rac1, and Cdc42, have emerged as key regulators of cadherin-mediated cell?cell adhesion.

  • Evidence indicates that Rho GTPases could influence cadherin-mediated cell?cell adhesion in many ways, for example by directly acting on components of the E-cadherin?β-catenin?α-catenin complex, recycling E-cadherin back to the cell surface after endocytosis and promoting E-cadherin cleavage by acting on a metalloproteinase.

  • p120ctn can modulate the activities of Rho GTPases, which leads to morphological change and increased cell migration. Tyrosine phosphorylaton of β-catenin, p120ctn and E-cadherin is thought to be involved in the regulation of cadherin-mediated cell?cell adhesion. As crosstalk occurs between Rho GTPases and tyrosine kinases during formation of integrin-mediated cell?substratum adhesions, it is possible that Rho GTPases might also participate in the signalling pathway between the cadherin?catenin complex and tyrosine kinases.

  • Studies have suggested that regulation of cadherin adhesion by Rho GTPases is important during synaptogenesis and synaptic plasticity in neuronal cells as well as epithelial cells. It is also conceivable that the dysregulation of this mechanism could be a cause of tumour metastasis.

Abstract

Cell?cell adhesions are rearranged dynamically during tissue development and tumour metastasis. Recently, Rho-family GTPases, including RhoA, Rac1 and Cdc42, have emerged as key regulators of cadherin-mediated cell?cell adhesion. Following the identification and characterization of regulators and effectors of Rho GTPases, signal transduction pathways from cadherin to Rho GTPases and, in turn, from Rho GTPases to cadherin, are beginning to be clarified.

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Figure 1: Dynamic rearrangements of cell?cell adhesion.
Figure 2: Cadherin-mediated cell?cell adhesion.
Figure 3: Regulation of Rho-family GTPases.
Figure 4: Role of IQGAP1 in the regulation of E-cadherin-mediated cell?cell adhesion.
Figure 5: Possible modes of action of Rho GTPases in the regulation of E-cadherin-mediated cell?cell adhesion.
Figure 6: Mode of activation of Rac1 by the formation of E-cadherin-mediated cell?cell adhesion.
Figure 7: Hypothetical model for the roles of p120ctn in the modulation of Rho GTPase activity.

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Acknowledgements

The authors thank M. Takeichi (Kyoto University) for critical reading and helpful discussion on the manuscript and A. Hall (University College London), J. G. Collard (The Netherlands Cancer Institute), K. Burridge (University of North Carolina), D. B. Sacks (Brigham and Women's Hospital and Harvard Medical School), N. A. Hotchin (University of Birmingham), A. B. Reynolds (Vanderbilt University), L. Y. Bourguignon (University of Miami), H. Saya (Kumamoto University) and A. D. Bershadsky (The Weizmann Institute of Science) for sending a preprint of work in press. We also thank S. Kuroda, M. Nakagawa, N. Itoh, M. Yamaga and the members of our laboratory for preparing the manuscript. The original work by the authors was supported by grants-in-aid for scientific research from the Ministry of Education, Science, Sports and Culture of Japan and by grants from Research for the Future of the Japan, Society for the Promotion of Science and Kirin Brewery Company Limited.

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Authors and Affiliations

  1. Department of Cell Pharmacology, Graduate School of Medicine, Nagoya University, 65 Tsurumai, Showa, 466-8550, Nagoya, Japan

    Masaki Fukata & Kozo Kaibuchi

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  1. Masaki Fukata
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  2. Kozo Kaibuchi
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Correspondence to Kozo Kaibuchi.

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DATABASES

Interpro:

cadherin domain

SH2

SH3

 LocusLink:

Ack

α-catenin

Cdc42

citron

E-cadherin

EGFR

Fer

KIAA0705

LARG

MAGI-1

MRCK

p120ctn

PAK

PDZ-RhoGEF

Por1

POSH

sif

Src

STEF

TNF-α receptor

 Swiss-Prot:

β-catenin

C-cadherin

CD44

GFP

heparin-binding epidermal growth factor

IQGAP1

IQGAP2

MMP-2

PTP-μ

Rac1

RhoA

RhoG

Rhotekin

SHP-1

SHP-2

Tiam1

Vav2

WASP

Glossary

COMPACTION

A process that is unique to mammalian embryonic cleavage, in which the blastomeres move closely together after the third cleavage to form a compact sphere. Tight junctions form between the outer-sphere cells, whereas cells inside form gap junctions, which facilitate the passage of small molecules and ions between the cells.

SYNAPTOGENESIS

The formation of a synaptic contact, a process involving elongation of the nerve process, recognition of guidance molecules by the growth cone and identification of the target.

KERATINOCYTES

Differentiated epithelial cells of the skin.

OPTICAL TWEEZERS

Focused photon fields.

SINGLE-PARTICLE TRACKING

A technique used to study the lateral composition of the plasma membrane of cells, in particular the movement of individual components.

CLASSIC CADHERINS

(For example, E-, N-, P- and R-cadherin.) A subfamily of cadherins that share a common primary structure and bind to catenins through conserved cytoplasmic domains.

FAT-LIKE CADHERINS

(For example, FAT1 and FAT2.) A subfamily of cadherins that contain large tandem arrays (19?34) of extracellular cadherin domains, a globin domain and an EGF domain.

SEVEN-PASS TRANSMEMBRANE CADHERINS

A subfamily of cadherins that show some similarity to the secretin family of G-protein- linked receptors and contain eight to nine extracellular cadherin domains, two globin domains and four EGF domains. Also present is a domain called the Flamingo box, which is located between the last extracellular cadherin domain and the first EGF domain and is highly conserved across species in this subfamily.

CIS DIMER

A dimer on the same membrane.

TRANS DIMER

A dimer on the facing membrane.

EGTA

Ethylenebis (oxyethylene-trinitrilo)tetraacetic acid. A chelating agent with a high affinity for Ca2+ ions.

ARMADILLO REPEAT

A sequence of 42 amino acids repeated in tandem that was first identified in the Drosophila segment polarity gene armadillo.

L FIBROBLAST

A mouse fibroblast line derived from connective tissue that does not express adhesion molecules.

GASTRULATION

A series of morphogenetic movements observed during the early development of most animals that leads to the formation of a multilayered embryo with an outer cell layer (ectoderm), an inner cell layer (endoderm), and an intermediate cell layer (mesoderm).

APICAL PLASMA MEMBRANE

The surface of an epithelial cell that faces the lumen of a cavity or tube.

PDZ DOMAIN

Protein interaction domain that often occurs in scaffolding proteins and is named after the founding members of this protein family (PSD-95, discs-large and ZO-1).

HYPERPLASIA

The increase in the size of a tissue or organ, which results from an increase in the total number of cells present. The part that is affected retains its normal form.

DYSPLASIA

Disordered growth: that is, an abnormally organized cell. The alterations include size, shape (pleomorphism), hypochromatic nuclei, and also architectural orientation of adult cells, which generally represents a premalignant stage.

METALLOPROTEINASE

Proteinase that has a metal ion at its active site.

ADP RIBOSYLATION

The transfer, through an ADP ribosyltransferase, of one or more ADPribosyl groups from NAD+ to a protein.

NEURITE EXTENSION

The process by which a nerve cell can give rise to an axon or a dendrite.

STRESS FIBRE

Axial bundle of F-actin that underlies the cell bodies.

FILOPODIUM

Finger-like exploratory cell extension found in crawling cells and growth cones.

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Fukata, M., Kaibuchi, K. Rho-family GTPases in cadherin-mediated cell — cell adhesion. Nat Rev Mol Cell Biol 2, 887–897 (2001). https://doi.org/10.1038/35103068

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