Regulation of cell–cell junctions by the cytoskeleton

Regulation of cell–cell junctions by the cytoskeletonRene-Marc Mege1, Julie Gavard2,* and Mireille Lambert1,*

A major form of animal cell–cell adhesion results from the

dynamic association of cadherin molecules, cytosolic catenins

and actin microfilaments. Cadherins dynamically regulate the

cytoskeleton. In turn, the actin cytoskeleton contributes to

cadherin molecule oligomerization at cell contacts and to cell

reshaping in response to environmental changes. Over the past

two years, this evolutionarily conserved adhesion system has

been intensively revisited in both its structural and functional

aspects; this is illustrated by the remarkable progress in the

determination of physical parameters of cadherin bonds

(including force measurement) and the new insights into the

role of a-catenin and the regulation of actin dynamics at

cadherin contacts. Other recent studies uncover the important

contribution of acto-myosin, microtubules and cell tension to

adherens junction formation, cell differentiation and tissue

reshaping/remodeling. An open challenge is now to integrate

these new data with the diversity of cadherin adhesive

complexes.

Addresses1 INSERM, U 706, Institut du Fer a Moulin, 75005 Paris, France;

Universite Pierre et Marie Curie-Paris6, 75005 Paris, France2 Present address: Oral and Pharyngeal Cancer Branch, National

Institute of Dental and Craniofacial Research, National Institutes of

Health, DHHS, Bethesda, Maryland 20892-4340*J Gavard and M Lambert contributed equally to this manuscript.

Corresponding author: Mege, RM ([email protected])

Current Opinion in Cell Biology 2006, 18:541–548

This review comes from a themed issue on

Cell-to-cell contact and extracellular matrix

Edited by Alpha Yap and Martin Schwartz

Available online 14th August 2006

0955-0674/$ – see front matter

# 2006 Elsevier Ltd. All rights reserved.

DOI 10.1016/j.ceb.2006.08.004

IntroductionTo assume a specific shape within tissues, to adapt this

shape in response to environmental, chemical and

mechanical changes, or to migrate, animal cells need to

tightly coordinate cell–cell adhesion with cytoskeleton

changes. This regulation is crucial in processes that occur

during the life of many types of cell: epithelial (polarity,

migration, carcinogenesis, etc), endothelial (angiogenesis,

barrier function, leukocyte transmigration, etc), mesench-

ymal/tumorigenic (migration) and neuronal (growth cone

migration, synapse function, etc). In this review, we will

focus on the most universal adhesion system leading to

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strong cell–cell interactions in animal cells: calcium-

dependent cell adhesion mediated by cadherins. This

adhesion system, best known for E-cadherin-mediated

adherens-type intercellular junctions, has recently proven

to be an essential cytoskeleton-regulated mode of cell

communication in various developmental and pathologi-

cal contexts [1]. Since the early experiments by Naga-

fuchi and Takeichi [2] demonstrating that the cadherin

cytoplasmic tail is needed for efficient cell aggregation,

and soon after the discovery of catenins as cytoplasmic

proteins associated with cadherin tails [3], the largely

accepted model is that cadherin/b-catenin complex binds

a-catenin which in turn recruits actin filaments. This old

idea was challenged recently by impressive biochemical

data, which prompt one to reconsider this feature from a

more dynamic perspective [4].

Over the two past years, the use of reductionist

approaches recapitulating some of the major events in

cell–cell contact formation together with technological

advances in cell imaging and biophysics brought major

breakthroughs. In particular, new concepts emerged

regarding how cytoskeleton-dependent scaffolding of

cadherins and cadherin-associated proteins beneath the

plasma membrane contributes to cell contact formation in

addition to adhesive bonds between cadherin ectodo-

mains. The molecular and dynamic coordination of these

two processes initiated by cadherin homophilic liganding

allows cells to regulate the extension and strengthening of

cell contacts [5], leading either to typical adherens junc-

tion formation in epithelia or to the maintenance of cell

contacts in more immature state in loosely adhesive or

migrating cells [6]. The implications of small GTPase

signaling, which were nicely reviewed last year [7], will

not be discussed here. Our objective here is to try to

reconcile in a shared mechanistic molecular view the

similar and divergent cytoskeleton-linked pathways lead-

ing to cadherin contact formation and intercellular junc-

tions in both epithelial and non-epithelial cells.

Initiating the contact: from free receptors tothe first adhesive bondsCell contact initiation requires fast, highly dynamic inter-

actions between cadherin receptors; this relies on deter-

minant parameters, including the availability of cadherin

receptors at the plasma membrane, their mobility, and the

ability of their intracellular and extracellular domains to

form protein–protein bonds. Trafficking of cadherin

towards and out of the membrane, which has recently

been reviewed elsewhere [8], will not be discussed here.

Cadherin receptors diffuse freely at the cell surface

before engagement into contacts, and then become


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http://dx.doi.org/10.1016/j.ceb.2006.08.004

542 Cell-to-cell contact and ECM

clustered by diffusion-trapping and limited in their move-

ment when committed in adhesive bonds by contact with

either cells or biomimetic surfaces [5,9–11]. Several high-

resolution biophysical approaches have been used pre-

viously to investigate cadherin–cadherin interactions at

the level of individual molecules in cell-free systems,

converging to the conclusion that single adhesive bonds

exhibit a short half-life (in the range of seconds) and

develop forces in the tens of picoNewtons (for review, see

[12]). This fast kinetic model was challenged in the

cellular context, either by keeping a tight control of

cadherin homophilic ligand presentation or by investigat-

ing direct cell–cell contacts using FRAP analysis. These

studies indicate that, in living cells, adhesive bonds based

on E-cadherin, N-cadherin and probably cadherin-11

display half-lives in the range of tens of minutes or greater

[11,13,14��]. Measurement of cell separation forces indi-

cates values in the tens of nanoNewtons [15��,16]. This

stabilization is only conceivable with an oligomerization

of cadherins rendered possible in a cellular context.

Mutant cadherin analysis and pharmacology demonstrate

that actin actively participates in the multiplication of

single unstable cadherin–cadherin bonds to generate

stable cell contacts [11,15��]. We will discuss below the

molecular correlates of such a phenomenon. However, it

remains clear that the extracellular domain is the primary

determinant of force developed by cadherin type I and

type II [16,17], correlating with differences in the struc-

tural features of the adhesive interface [18].

An open issue is the requirement for the association of

cadherin with actin in the very initial steps of contact

formation. The molecular model suggesting that the

cadherin/actin link results from direct cadherin/b-cate-

nin/a-catenin interactions was re-examined by a recent

biochemical analysis and in vitro reconstruction of the

cadherin/catenin complex [14��,19], in which a-catenin

could not be found in interaction simultaneously with

actin and E-cadherin/b-catenin. Accordingly, a-catenin

may associate with freely diffusible unengaged cadherin

cis-dimers but not directly with cadherins involved in

adhesive bonds. Nevertheless these engaged cadherins

are mechanically linked to the actin flow [9]. Clearly, the

cadherin/actin interaction is mediated through a more

complex network of protein–protein interactions and/or

other unidentified partners.

It is noteworthy that the initiation of cell contact relies

on direct signaling triggered by cadherin engagement

(Figure 1). Studies over recent years have clearly shown

that activation of Rac and Arp2/3-dependent actin nuclea-

tion follow the formation of the first adhesive bonds

[20,21�]. Cortactin is also recruited in a Rac-dependent

manner at nascent cadherin contacts [22�,23], then phos-

phorylated on tyrosine by the non-receptor tyrosine

kinase Fer [24], itself recruited in cadherin complexes

[25]. Cortactin may act as a scaffold protein linking Arp2/3


to actin and stimulating its activity. Whether active actin

polymerization is solely triggered locally by cadherin

engagement or whether cadherin adhesive bonds form

in regions of the cell characterized by pre-existing active

actin dynamics remains an open question [9].

Extending the contact: zipping themembranesWhen cells make contact, driven either by the mechanical

pressure of their environment or by an active migration

process, the most obvious response is the induction of

lamellipodial extension driven by local Rac activation

[21�,26–28]. The initial engagement of a few cadherins

may be the most important event for maintaining the high

membrane remodeling and actin dynamics necessary for

the enhanced lamellipodial protrusion and the associated

cell contact extension (Figure 2). Indeed, while this

lamellipodial activity relies on a cell spreading pathway

commonly activated by various stimuli in different cel-

lular contexts, silencing experiments indicate that p120 is

essential to provide proper and restricted Rac localization

[21�]. In addition to Arp2/3, E-cadherin liganding also

recruits Mena at the leading edge, and both Arp2/3 and

Ena/VASP activities are necessary in turn for contact

extension [29,30]. Interestingly, the FAT1 protocadherin

binds to Ena/VASP and cooperates with classical cadher-

ins to regulate actin dynamics at cadherin contacts

[31,32]. The branching and polymerization of actin cat-

alyzed by Arp2/3 and Mena may provide the driving force

that pushes the membranes of adjacent cells over each

other.

Alternatively, another type of actin polymerization gen-

erating unbranched long filaments — that is catalyzed by

formin [33] — may also be involved in contact extension

via the formation of filopodia, frequently observed at cell–

cell contacts. Indeed, formin-1 is localized at adherens

junctions and binds directly to a-catenin, allowing the

formation of radial actin cable and the stabilization of the

junction [34]. Formin and Ena/VASP activities may coop-

erate to extend filopodia [35] and future studies may

address whether formin-catalyzed actin polymerization

participates in cadherin contact extension.

Strengthening the contact: an oligomericcomplex assembled along actin bundlesChu et al. [15��,16] directly measured the strength of

cadherin-mediated cell contacts, showing a several-fold

increase in separation forces over a 30 minute period. This

cell contact maturation, which strongly depends on Rac

and Cdc42 activities as well as on cadherin sub-type,

density and linkage to actin, cannot be explained solely

by an increased cell contact area but strongly indicates

regulated cadherin/catenin/actin scaffold remodeling.

One can be left with two hypotheses: association with

actin strengthens the contact and/or cooperative cadherin

oligomerization stabilizes cadherin trans-interactions. No


Regulation of cell–cell junctions by the cytoskeleton Mege, Gavard and Lambert 543

Figure 1

The initial step of cadherin contact formation and associated signaling (hypothetical view based on references cited below and inspired by

[20,68]). A proposed pathway for the actin remodeling at nascent cell contacts starts with cadherin engagement. Cadherin homophilic liganding

induces a PI3-kinase-dependent Rac 1 activation (grey arrows indicate putative recruitment and activation of Rac1 and PI3-kinase by cadherin/catenin

complexes) [21�,69]. Arp2/3-mediated actin nucleation is stimulated by Rac1 effectors [28] and/or by the recruitment of cortactin at the cell

margin [22�,23]. The non-receptor Fer kinase associates to the cadherin–catenin complex via p120 [25]. Once activated, Fer phosphorylates

cortactin on tyrosine 421 [24]. Phosphorylated cortactin stimulates the actin branching activity of Arp2/3 complex, leading to the formation of a

branched meshwork of actin. In addition, Mena (Mammalian Ena/VASP homolog [38]) recruited by cadherin activation together with Arp2/3 may

increase actin polymerization through its association with profilin and anti-capping activities, enhancing the incorporation of actin monomers at

barbed ends [29]. The actin severing protein gelsolin was also shown to be recruited at cadherin contacts and to contribute to actin polymerization

by generating new barbed ends available for actin polymerization [70]. Together, these pathways may contribute to sustaining fast actin dynamics

and cadherin mobilization at nascent contacts.

definitive molecular explanation is available so far. How-

ever, recent studies clearly show that in older cadherin

contacts, cadherins are recruited in highly patterned

protein scaffolds tightly anchored to actin cables, named

cadherin adhesions or macroclusters [21�,36,37]. The

formation of these structures, which probably correspond

to the puncta observed years ago at cell–cell contacts by

Adams and Nelson [5], may support the time-dependent

increase of cadherin contact strength, as determined by

separation force measurement [15��]. The transition

between expanding nascent contacts associated with

Arp2/3 branched actin and cadherin adhesions associated

with actin cables would primarily rely on a local change in

actin dynamics regulated by the absence of Arp2/3 and

the presence of Ena/VASP [29] activities (Figure 2), in

agreement with the observed increased actin branching in

Ena/VASP-deficient fibroblasts from double mutant

mouse embryos [38]. In addition, a-catenin was recently

proposed as a potential switch in this process. The studies

of the Nelson and Weis groups argue in favor of antag-

onistic binding properties of a-catenin monomers to


E-cadherin/b-catenin complex and a-catenin dimers to

actin [14��,19]. Dimers of a-catenin may regulate the

transition between cortical branched filaments at nascent

contacts to actin bundles in mature contacts, by compet-

ing with the Arp2/3 complex and possibly acting as an

actin crosslinker [19]. Vinculin could collaborate here

with a-catenin. Indeed, recent structural and biochemical

analysis suggests a model for the activation of vinculin at

cell–cell contacts. Vinculin spontaneously adopts an auto-

inhibited conformation characterized by an intramolecu-

lar interaction of C- and N-terminal domains. Upon cell

adhesion, vinculin bound in a ternary complex with actin

and a-catenin becomes activated by breakage of this

head-to-tail interaction and subsequent opening of the

molecule [39], thereby allowing the vinculin tail to dimer-

ize and crosslink actin filaments, favoring the formation of

actin bundles [40].

It has been shown that VE-cadherin can be recruited in

clusters in the absence of actin interactions, probably

under the action of cell membrane tension [41].



Figure 2

Cadherin contact extension and strengthening (hypothetical view based on references cited below and inspired by [19,71]). In an appealing

model, cadherin contacts may initiate preferentially in highly dynamic membranes such as lamellipodia and filopodia and, by sustaining a

high actin turnover, favor the extension of the cell–cell contact and proper concentration of cadherin receptors at the nascent contact zones.

Cis-dimers of cadherin/b-catenin/a-catenin presented by lamellipodia of neighboring cells make contact and the first cadherin adhesive bonds

are formed. As a consequence, Arp2/3, cortactin and Mena are recruited at nascent contacts and localize at the outer cell margin of the lamellipodium

(see Figure 1 for detailed signaling pathways), where they enable proper actin dynamics to generate the pushing force driving cell membrane

protrusion. As a consequence, adjacent cells send reciprocal lamellipodia, leading to the extension of the contact area by mobilization of

additional cadherin molecules [21�,26,28]. Actin polymerization at the tip of the lamellipodia together with actin filament contraction through

myosin II activity [37] support the continuous rearward flow of the actin cytoskeleton. Once engaged, cadherin molecules become anchored

to this rearward-moving actin treadmilling [9], which facilitates their recruitment in large clusters aligned along actin cables (which have been

named cadherin adhesions by us and macroclusters by others) [21�,29]. During this process, under the control of actin unbranching and

cross-linking proteins, the actin network re-organizes to progressively form bundles. Mena could participate in filament unbranching by inhibiting

Arp2/3 or reducing branch stability [29]. a-catenin, unable to efficiently bind to cadherin/b-catenin complex, is released locally as dimers and,

by competing with Arp2/3 activity, may induce a switch from cortical branched filaments to actin bundles [14��,19]. Vinculin may collaborate with

a-catenin to stabilize actin bundles [40], while Myosin II may contribute to their contraction, thus promoting cadherin adhesion stabilization [37].

Following E-cadherin trans-interaction, myosin II is

recruited and phosphorylated, supporting the further

recruitment of E-cadherin molecules [37], which suggests

a primordial role for acto-myosin. Myosin II may con-

tribute to the establishment of membrane tension as well

as to the contraction and rearward movement of actin

cytoskeleton, literally dragging cadherin molecules in

cadherin adhesions. Another myosin, myosin VII, which

bridges cadherin to the transmembrane protein vezatin,

was proposed to increase the tension between the plasma

membrane and the cytoskeleton [42]. Vezatin is required

for extended E-cadherin-dependent cell–cell interactions

in mouse preimplantation development [43]. Alterna-

tively, vezatin, together with myosin VIIa, may indepen-

dently initiate a signalling cascade including Arf6 and

ARHGAP10, leading to the control of a-catenin localiza-

tion at cell–cell contacts [44]. In the Drosophila embryo,


the unconventional myosin VI is involved in DE-cad-

herin-dependent border cell migration, where it is

thought to produce protrusive forces on the plasma

membrane [45]. The involvement of myosin VI has

recently been documented during dorsal closure [46].

Future studies are needed to resolve the role of this

unconventional myosin in mammals.

Reshaping the cell: forming adherensjunctions or zonula adherens and anchoringmicrotubules to the cell cortexCadherin adhesions are further regulated by cell-specific

mechanical and biochemical constraints. For instance,

epithelial and endothelial cells require a strong and

polarized adhesion, whereas fibroblasts and neuronal cells

are involved in more plastic and labile interactions

[1,47,48]. This is probably reflected by the specific



composition of the associated cadherin complexes and

also by the specific architecture of the cytoskeleton.

However, we would like to propose the idea that the

initial steps of contact formation described above are

common to most of these cells, while contact maturation

and reshaping are divergent. For example, while cadherin

adhesions have never been detected in moving growth

cones [49], non-polarized fibroblast-like and polarized

epithelial cells eventually organize cadherin contacts in

typical intercellular junctions with, however, defined

ultra-structural differences (Figure 3): in other words,

they are associated with radial actin filaments in fibro-

blastic adherens junctions and with tangential actin bun-

dles in epithelial zonula adherens [6].

Recent reports demonstrate the involvement of myosin II

in bringing the tangential contractile actomyosin rings in

close contact with E-cadherin adhesions and converting

them into typical zonula adherens. Myosin II, phosphory-

lated in a microtubule-dependent manner upon E-cad-

herin liganding [37,50], contributes to the organization of

zonula adherens itself and to the further formation of

zonula occludens and the generation of the columnar

shape of fully polarized epithelial cells [51�,52]. In vivo,

Figure 3

Adherens junction formation in non-polarized cells: transient and final step f

[52,72]). Non-epithelial cells organize typical adherens junctions (a) defined

actin cables. However, most of the time, cell–cell contacts do not evolve fu

macroclusters), which may be confusingly called intercellular junctions or ad

contacts are perpendicular to the membrane [6]. Fibroblasts (a) and polarized

with typical zonula adherens forming only in the latter [6]. Polarized epithelia

and, in addition, organize a large ring of contractile actin bundles (b) that bec

Myosin II brings the contractile actomyosin ring in close contact with radial-

zonula adherens [37,51�]. Myosin II activation by phosphorylation has been

on microtubule stability [37,50]. Thus, myosin II participates both in the form

occludens and the generation of the columnar regular shape of fully polarize


it has been suggested that myosin II contributes to

intercalation processes by generating local forces leading

to polarized remodeling of cell junctions in Drosophila[53]. Myosin IIA-negative mouse embryos display defects

in mesoderm polarization associated with a loss of cad-

herin concentration at cell–cell contacts [54]. Interest-

ingly, in the Ca2+ switch model, intercellular junction

disruption (by the simultaneous breaking and internaliza-

tion of cadherin bonds) and intercellular junction refor-

mation rely on directly opposite processes involving the

microtubule cytoskeleton and myosin II-dependent con-

traction of the actomyosin ring [50,51�,52,55,56]. While

recapitulating important final steps in adherens junction

formation, as demonstrated earlier in keratinocytes [57],

contact reformation in these conditions bypasses the

initial steps of contact extension and maturation. Inter-

estingly, this model mimics the extrusion of apoptotic

cells from an epithelial sheet that occurs during main-

tenance of the trans-epithelial barrier, which relies on a

very similar process [56].

The microtubule network is as well an important element

of cell architecture. It has been shown that microtubules

reach adherens junctions with their plus end [58] and that

or zonula adherens formation in polarized epithelia (inspired from

by ultrastructurally recognizable intercellular junctions enriched in

rther and cells form extended cadherin adhesions (or puncta, or

herens junctions. In both cases, actin cables anchored to cadherin

epithelial cells (b,c) greatly differ in their actin cytoskeleton organization,

l cells form cadherin adhesions associated to radial actin cables,

omes tightly associated to cadherin contacts at the zonula adherens (c).

actin-associated E-cadherin adhesions to transform them in typical

shown to be initiated by E-cadherin liganding by a process depending

ation of the junction itself and in the further formation of zonula

d epithelial cells [51�,52].



cadherin contacts stabilize non-centrosomally anchored

microtubules through their minus ends, but proteins

regulating these dynamic interactions remain to be iden-

tified [59]. Among others, kinesin has been shown to

interact with p120 [60] and dynein with b-catenin [61].

Two recent studies confirm these early findings and show

that microtubules are necessary for cadherin contact for-

mation together with myosin II [50], while adherens

junction disassembly requires myosin II and kinesin 1

[56]. While these results do indicate crosstalk between

microtubule-associated motors and actin-associated cad-

herin contacts [62], this research field is only slowly

emerging. The implications are interesting, as illustrated

by the fact that the asymmetrically distributed DE-cad-

herin in Drosophila regulates the orientation of cell divi-

sions in sensory organ [63].

To conclude, the fact that closely related cadherin mem-

bers, often the same molecule, are involved in processes

as diverse as mesenchymal cell contacts, epithelial/

endothelial junction formation, cell intercalation, growth

cone progression and synaptogenesis [1] highlights the

importance of cell- and physiology-specific cadherin part-

ners. Accordingly, more and more proteins are expected

to be discovered to regulate cadherin contacts. Along

these lines, the immunoglobulin family adhesion mole-

cules nectins and their actin-associated partners afadins

have been involved in the organization of adherens junc-

tions [64]. A recent report strengthens the idea that

nectins positively regulate adherens and tight junctions

in MDCK cells [65]. Moreover, the nectin-like protein

echinoid in Drosophila cooperates positively with DE-

cadherin in the formation of adherens junctions [66].

However, the great importance of cadherin contacts for

epithelial polarity and apical complex formation in vivohas been recently demonstrated in mice conditionally

deleted for aE-catenin in neuroepithelial cells [67��].Interestingly, the same study unravels a drastic deregula-

tion of cell proliferation resulting from overstimulation of

the hedgehog pathway.

ConclusionsOver recent years, technological advances in cell imaging

and biophysics together with biochemical analyses have

greatly assisted our understanding of the regulation of cell

contacts by the cytoskeleton and vice-versa. Conversely,

along these years we switched from a four-piece puzzle to

a 40-piece puzzle, with the consequence that what

appeared so clear 10 years ago is indeed better understood

at the molecular level still seems very patchy and incom-

plete. Clearly, we need to know more about cadherin/

catenin complex structures. Also, data on dynamic pro-

tein–protein interactions in live cells are urgently

required. We can postulate that major conformational

changes will play a key role in the reciprocal regulation

of cell contact by actin dynamics. In the light of the

important role of these processes in cell shape, much


more remains to be discovered concerning cadherin/

microtubule relations. Finally, how these events are

linked to important adhesion-triggered signaling path-

ways controlling cell proliferation, differentiation and

survival will be the most important challenge of the

coming years.

AcknowledgementsWe would thank the members of the ‘‘Juxtacrine Cell Interactions’’ groupfor their patience and support during writing. We are immensely gratefulto Dr Andre Sobel, head of the department, for his continual support anddiscussions and for critical reading of the manuscript. The group issupported by institutional funding from INSERM (Institut National de laSante et de la Recherche Medicale), Universite Pierre et Marie Curie(Paris-6), as well as by grants from CNRS (Centre National de leRecherche Scientifique), AFM (Association Francaise contre lesMyopathies) and ARC (Association Francaise de Recherche contre leCancer).

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14.��

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15.��

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21.�

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22.�

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This study assigns a new role to the cytoskeletal/trafficking regulatoryprotein cortactin. Cortactin is recruited to cell contacts in response to E-cadherin homophilic liganding. In the absence of cortactin or when itsfunction is altered, Arp2/3-dependent actin polymerization is blocked andcell contacts do not extend and organize properly.

23. El Sayegh TY, Arora PD, Laschinger CA, Lee W, Morrison C,Overall CM, Kapus A, McCulloch CA: Cortactin associateswith N-cadherin adhesions and mediates intercellularadhesion strengthening in fibroblasts. J Cell Sci 2004,117:5117-5131.

24. Sayegh TY, Arora PD, Fan L, Laschinger CA, Greer PA,McCulloch CA, Kapus A: Phosphorylation of N-cadherin-associated cortactin by Fer kinase regulates N-cadherinmobility and intercellular adhesion strength. Mol Biol Cell 2005,16:5514-5527.

25. Xu G, Craig AW, Greer P, Miller M, Anastasiadis PZ, Lilien J,Balsamo J: Continuous association of cadherin with b-catenin


requires the non-receptor tyrosine-kinase Fer. J Cell Sci 2004,117:3207-3219.

26. Ehrlich JS, Hansen MD, Nelson WJ: Spatio-temporalregulation of Rac1 localization and lamellipodia dynamicsduring epithelial cell-cell adhesion. Dev Cell 2002,3:259-270.

27. Hoshino T, Shimizu K, Honda T, Kawakatsu T, Fukuyama T,Nakamura T, Matsuda M, Takai Y: A novel role of nectins ininhibition of the E-cadherin-induced activation of Rac andformation of cell-cell adherens junctions. Mol Biol Cell 2004,15:1077-1088.

28. Kovacs EM, Goodwin M, Ali RG, Paterson AD, Yap AS:Cadherin-directed actin assembly: E-cadherin physicallyassociates with the Arp2/3 complex to direct actin assemblyin nascent adhesive contacts. Curr Biol 2002, 12:379-382.

29. Scott JA, Shewan AM, Den Elzen NR, Loureiro JJ, Gertler FB,Yap AS: Ena/VASP proteins can regulate distinct modes ofactin organization at cadherin-adhesive contacts. Mol Biol Cell2006, 17:1085-1095.

30. Verma S, Shewan AM, Scott JA, Helwani FM, Den Elzen NR,Miki H, Takenawa T, Yap AS: Arp2/3 activity is necessaryfor efficient formation of E-cadherin adhesive contacts.J Biol Chem 2004, 279:34062-34070.

31. Tanoue T, Takeichi M: Mammalian Fat1 cadherin regulatesactin dynamics and cell–cell contact. J Cell Biol 2004,165:517-528.

32. Moeller MJ, Soofi A, Braun GS, Li X, Watzl C, Kriz W, Holzman LB:Protocadherin FAT1 binds Ena/VASP proteins and isnecessary for actin dynamics and cell polarization. EMBO J2004, 23:3769-3779.

33. Kovar DR: Molecular details of formin-mediated actinassembly. Curr Opin Cell Biol 2006, 18:11-17.

34. Kobielak A, Pasolli HA, Fuchs E: Mammalian formin-1participates in adherens junctions and polymerization of linearactin cables. Nat Cell Biol 2004, 6:21-30.

The authors shows that mammalian formin-1 localizes to adherensjunctions, and it directly binds a-catenin and nucleates unbranched actinfilaments essential for the formation of radial actin cables and thestabilization of adherens junctions in epithelial cells.

35. Schirenbeck A, Arasada R, Bretschneider T, Schleicher M, Faix J:Formins and VASPs may co-operate in the formation offilopodia. Biochem Soc Trans 2005, 33:1256-1259.

36. de Rooij J, Kerstens A, Danuser G, Schwartz MA,Waterman-Storer CM: Integrin-dependent actomyosincontraction regulates epithelial cell scattering. J Cell Biol2005, 171:153-164.

37. Shewan AM, Maddugoda M, Kraemer A, Stehbens SJ, Verma S,Kovacs EM, Yap AS: Myosin 2 is a key Rho kinase targetnecessary for the local concentration of E-cadherin at cell–cellcontacts. Mol Biol Cell 2005, 16:4531-4542.

38. Krause M, Dent EW, Bear JE, Loureiro JJ, Gertler FB: Ena/VASPproteins: regulators of the actin cytoskeleton and cellmigration. Annu Rev Cell Dev Biol 2003, 19:541-564.

39. Bakolitsa C, Cohen DM, Bankston LA, Bobkov AA, Cadwell GW,Jennings L, Critchley DR, Craig SW, Liddington RC: Structuralbasis for vinculin activation at sites of cell adhesion.Nature 2004, 430:583-586.

40. Janssen ME, Kim E, Liu H, Fujimoto LM, Bobkov A, Volkmann N,Hanein D: Three-dimensional structure of vinculin bound toactin filaments. Mol Cell 2006, 21:271-281.

By a combination of electron microscopy, computation and biochemistry,this work provides a model at the atomic level of how the vinculin tail bindsto actin. The proposed model involves the activation of vinculin by head/tail opening, initiated in a ternary complex formed by vinculin, actin and a-catenin. Activation renders vinculin available for homodimerisation (tail–tail) and heterodimerisation with a-catenin (through the vinculin head). Asa consequence, the affinity of vinculin as well as a-catenin for actin isenhanced.

41. Delanoe-Ayari H, Al Kurdi R, Vallade M, Gulino-Debrac D,Riveline D: Membrane and acto-myosin tension promote



clustering of adhesion proteins. Proc Natl Acad Sci U S A 2004,101:2229-2234.

42. Kussel-Andermann P, El Amraoui A, Safieddine S, Nouaille S,Perfettini I, Lecuit M, Cossart P, Wolfrum U, Petit C: Vezatin, anovel transmembrane protein, bridges myosin VIIA to thecadherin–catenins complex. EMBO J 2000, 19:6020-6029.

43. Hyenne V, Louvet-Vallee S, El Amraoui A, Petit C, Maro B,Simmler MC: Vezatin, a protein associated to adherensjunctions, is required for mouse blastocyst morphogenesis.Dev Biol 2005, 287:180-191.

44. Sousa S, Cabanes D, Archambaud C, Colland F, Lemichez E,Popoff M, Boisson-Dupuis S, Gouin E, Lecuit M, Legrain P et al.:ARHGAP10 is necessary for a-catenin recruitment atadherens junctions and for Listeria invasion. Nat Cell Biol 2005,7:954-960.

45. Geisbrecht ER, Montell DJ: Myosin VI is required for E-cadherin-mediated border cell migration. Nat. Cell Biol 2002, 4:616-620.

46. Millo H, Leaper K, Lazou V, Bownes M: Myosin VI plays a role incell–cell adhesion during epithelial morphogenesis. Mech Dev2004, 121:1335-1351.

47. Takeichi M, Abe K: Synaptic contact dynamics controlled bycadherin and catenins. Trends Cell Biol 2005, 15:216-221.

48. Dejana E: Endothelial cell–cell junctions: happy together.Nat Rev Mol Cell Biol 2004, 5:261-270.

49. Marthiens V, Gavard J, Padilla F, Monnet C, Castellani V,Lambert M, Mege RM: A novel function for cadherin-11 inthe regulation of motor axon elongation and fasciculation.Mol Cell Neurosci 2005, 28:715-726.

50. Stehbens SJ, Paterson AD, Crampton MS, Shewan AM,Ferguson C, Akhmanova A, Parton RG, Yap AS: Dynamicmicrotubules regulate the local concentration of E-cadherin atcell–cell contacts. J Cell Sci 2006.

51.�

Zhang J, Betson M, Erasmus J, Zeikos K, Bailly M, Cramer LP,Braga VM: Actin at cell-cell junctions is composed of twodynamic and functional populations. J Cell Sci 2005,118:5549-5562.

This study focuses on two spatially and functionally distinct actin popula-tions involved in epithelial cell reshaping from a flat, spread shape to thecuboidal epithelial morphology. In contrast to cadherin-associated actinfilaments, thin actin bundles contract to increase the lateral cell heightand become spatially indistinguishable from junctional actin once mor-phological differentiation is achieved.

52. Ivanov AI, Hunt D, Utech M, Nusrat A, Parkos CA: Differentialroles for actin polymerization and a myosin II motor inassembly of the epithelial apical junctional complex.Mol Biol Cell 2005, 16:2636-2650.

53. Bertet C, Sulak L, Lecuit T: Myosin-dependent junctionremodelling controls planar cell intercalation and axiselongation. Nature 2004, 429:667-671.

54. Conti MA, Even-Ram S, Liu C, Yamada KM, Adelstein RS:Defects in cell adhesion and the visceral endoderm followingablation of nonmuscle myosin heavy chain II-A in mice.J Biol Chem 2004, 279:41263-41266.

55. Ivanov AI, McCall IC, Parkos CA, Nusrat A: Role for actin filamentturnover and a myosin II motor in cytoskeleton-drivendisassembly of the epithelial apical junctional complex.Mol Biol Cell 2004, 15:2639-2651.

56. Ivanov AI, McCall IC, Babbin B, Samarin SN, Nusrat A, Parkos CA:Microtubules regulate disassembly of epithelial apicaljunctions. BMC Cell Biol 2006, 7:12.


57. Vaezi A, Bauer C, Vasioukhin V, Fuchs E: Actin cable dynamicsand Rho/Rock orchestrate a polarized cytoskeletalarchitecture in the early steps of assembling a stratifiedepithelium. Dev Cell 2002, 3:367-381.

58. Waterman-Storer CM, Salmon WC, Salmon ED: Feedbackinteractions between cell-cell adherens junctions andcytoskeletal dynamics in newt lung epithelial cells. Mol BiolCell 2000, 11:2471-2483.

59. Chausovsky A, Bershadsky AD, Borisy GG: Cadherin-mediatedregulation of microtubule dynamics. Nat Cell Biol 2000,2:797-804.

60. Chen X, Kojima S, Borisy GG, Green KJ: p120 catenin associateswith kinesin and facilitates the transport of cadherin-catenincomplexes to intercellular junctions. J Cell Biol 2003,163:547-557.

61. Ligon LA, Karki S, Tokito M, Holzbaur EL: Dynein binds tob-catenin and may tether microtubules at adherens junctions.Nat Cell Biol 2001, 3:913-917.

62. Braga VM: Cell-cell adhesion and signalling. Curr Opin Cell Biol2002, 14:546-556.

63. Le Borgne R, Bellaiche Y, Schweisguth F: Drosophila E-cadherinregulates the orientation of asymmetric cell division in thesensory organ lineage. Curr Biol 2002, 12:95-104.

64. Takai Y, Nakanishi H: Nectin and afadin: novel organizers ofintercellular junctions. J Cell Sci 2003, 116:17-27.

65. Sato T, Fujita N, Yamada A, Ooshio T, Okamoto R, Irie K, Takai Y:Regulation of the assembly and adhesion activity ofe-cadherin by nectin and afadin for the formation of adherensjunctions in madin-darby canine kidney cells. J Biol Chem2006, 281:5288-5299.

66. Wei SY, Escudero LM, Yu F, Chang LH, Chen LY, Ho YH, Lin CM,Chou CS, Chia W, Modolell J, Hsu JC: Echinoid is a componentof adherens junctions that cooperates with DE-Cadherin tomediate cell adhesion. Dev Cell 2005, 8:493-504.

67.��

Lien WH, Klezovitch O, Fernandez TE, Delrow J, Vasioukhin V:aE-catenin controls cerebral cortical size by regulating thehedgehog signaling pathway. Science 2006, 311:1609-1612.

By generating a conditional knock-out of the a-catenin gene in mouseneuroepithelium, this group demonstrates the essential role of this cate-nin in the proliferation and organisation of brain cell precursors. A genearray approach suggests that the hedgehog pathway is affected. In aproposed model, the establishment of cell–cell contacts induces thedown-regulation of the hedgehog pathway once sufficient cell prolifera-tion is achieved. In the absence of adhesion complexes, activation of thehedgehog pathway is sustained, leading to uncontrolled cell proliferation.By a neat pharmacological treatment, the authors uncouple this effectfrom the effect of the lack of a-catenin on neuroepithelial cell polarizationleading to disorganized brain structure.

68. Troyanovsky S: Cadherin dimers in cell–cell adhesion. Eur J CellBiol 2005, 84:225-233.

69. Kovacs EM, Yap AS: The web and the rock: cell adhesion andthe ARP2/3 complex. Dev Cell 2002, 3:760-761.

70. Chan MW, El Sayegh TY, Arora PD, Laschinger CA, Overall CM,Morrison C, McCulloch CA: Regulation of intercellular adhesionstrength in fibroblasts. J Biol Chem 2004, 279:41047-41057.

71. Marthiens V, Gavard J, Lambert M, Mege RM: Cadherin-basedcell adhesion in neuromuscular development. Biol Cell 2002,94:315-326.

72. Zigmond S: Formin’ adherens junctions. Nat Cell Biol 2004,6:12-14.


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Regulation of cell–cell junctions by the cytoskeleton