Adherens Junction: Molecular Architecture and …cshperspectives.cshlp.org/content/1/6/a002899.full.pdfAdherens Junction: Molecular Architecture and Regulation Wenxiang Meng and Masatoshi

Adherens Junction: MolecularArchitecture and Regulation

Wenxiang Meng and Masatoshi Takeichi

RIKEN Center for Developmental Biology, Chuo-ku, Kobe 650-0047, Japan

Correspondence: [email protected]

The adherens junction (AJ) is an element of the cell–cell junction in which cadherinreceptors bridge the neighboring plasma membranes via their homophilic interactions.Cadherins associate with cytoplasmic proteins, called catenins, which in turn bind to cyto-skeletal components, such as actin filaments and microtubules. These molecular complexesfurther interact with other proteins, including signaling molecules, rendering the AJs intohighly dynamic and regulatable structures. The AJs of such nature contribute to the physicallinking of cells, as well as to the regulation of cell–cell contacts, which is essential formorphogenesis and remodeling of tissues and organs. Thus, elucidating the moleculararchitecture of the AJs and their regulatory mechanisms are crucial for understanding howthe multicellular system is organized.

The adherens junction (AJ) is a form ofcell–cell adhesion structure observed in a

variety of cell types, as well as in differentanimal species. It is characterized by a pair ofplasma membranes apposed with a distance of10–20 nm between them, whose intercellularspace is occupied by rod-shaped moleculesbridging the membranes (Hirokawa andHeuser 1981; Miyaguchi 2000), and the cyto-plasmic side of the AJ is associated with con-densed actin filaments. In polarized epitheliaof vertebrates, the AJ is part of the tripartitejunctional complex localized at the juxta-luminal region, which comprises the tight junc-tion (zonula occludens), AJ, and desmosome(macula adherens) aligned in this order fromthe apical end of the junction (Farquhar andPalade 1963). In this type of epithelia, the AJ

is specifically termed the “zonula adherens” or“adhesion belt,” as it completely encloses thecells along with the F-actin lining, called the cir-cumferential actin belt (Fig. 1). The AJs in othercell types assume different morphologies: Forexample, the AJs in fibroblastic cells are spottyand discontinuous (Yonemura et al. 1995),and those in neurons are organized into tinypuncta as a constituent of the synaptic junctions(Uchida et al. 1996).

A major function of AJs is to maintain thephysical association between cells, as disruptionof them causes loosening of cell–cell contacts,leading to disorganization of tissue architec-ture. Calcium chelators such as EDTA andEGTA are widely used as a reagent to promotethe dissociation of cells in tissues or monolayercultures. A major target of these chelators is the

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AJ, as this is a calcium-sensitive structure;although, calcium removal is generally insuffi-cient for the complete dispersion of cellsbecause of the presence of calcium-independentcell–cell adhesion mechanisms (Takeichi et al.1977). Early studies to search for the moleculesresponsible for the calcium-dependent junc-tions resulted in the identification of a groupof type-I transmembrane proteins, and itsfounding member was termed cadherin(Yoshida and Takeichi 1982; Yoshida-Noroet al. 1984). Related molecules identified werealso called by various names, such as uvomoru-lin (Peyrieras et al. 1983), LCAM (Gallin et al.1983), and ACAM (Volk and Geiger 1984).Later studies revealed that the cadherins forma superfamily, and therefore, the originalcadherins are now called “classic” cadherins.

Another series of studies have identifiednectins, a family of immunoglobulin-liketransmembrane proteins, as an AJ component.Nectins function in a calcium-independentway to promote cell–cell adhesion (Nakanishiand Takai 2004). In this article, we overviewthe molecular organization of the AJs con-structed with these membrane proteins, aswell as the regulatory mechanisms that operate

to sustain or remodel these junctions, payingmuch attention to the linkages between the AJand cytoskeletal or signaling proteins.

CADHERINS

The classic cadherin family comprises approx-imately 20 members that share a commondomain organization. The members are calledE-cadherin (cdh1), N-cadherin (cdh2), andso on, each of which shows a distinct tissuedistribution pattern (Takeichi 1988). Theirextracellular domain is divided into five re-petitive subdomains, called cadherin repeatsor EC domains, and each subdomain containscalcium-binding sequences (Overduin et al.1995). The interaction of calcium ions withthese sequences controls the conformation ofthe extracellular domain (Pokutta et al. 1994),switching its adhesive function “off” and “on.”On its association with calcium, the extra-cellular domain of cadherins on a cell undergoeshomophilic interaction with that of cadherinspresent on the apposed cells (Fig. 2). Theprecise mechanism for this homophilic inter-action is still controversial (Troyanovsky2005), although current studies support the

E-cadherin

Caco2

MCF10A

F-actin Merge

Figure 1. Morphological variations of the adherens junction. In Caco2 cells (colonic carcinoma line), E-cadherinis localized along the actin circumferential belt to organize the zonula adherens (arrow). At the lateral portions ofcell junction (arrowheads), E-cadherin signals are punctate, only occasionally overlapping with actin signals inthis specific sample. The lateral patterns of cadherin and actin distribution, however, vary with cellularconditions. In MCF10A cells (mammary epithelial line), spotty adherens junctions are seen, where actinfilaments perpendicularly terminate at E-cadherin puncta.

W. Meng and M. Takeichi

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idea that a trans binding between cadherinmonomers via their EC1 domains initiatestheir interactions (Zhang et al. 2009).

The calcium-sensitive sequences are highlyconserved among the family members, whosesequences are the hallmarks for this family,and all classic cadherins show a similar calciumdependence. Other sequences in the extracellu-lar domain, however, vary, and this sequencevariation confers the adhesive specificity oneach member (Nose et al. 1988). For example,E-cadherin preferentially binds E-cadherin,and N-cadherin does so to N-cadherin; al-though, the degree of the selectivity changesdepending on the partners (Shimoyama et al.2000; Patel et al. 2006). This nature of classiccadherins has been implicated in the sortingof different cell types (Takeichi 1988).

AJs occur in a wide variety of animal species,and classic cadherin-type molecules have beenidentified in many species (Oda et al. 2005).However, their molecular organization is notperfectly conserved. For example, althoughDrosophila E-cadherin (DE-cadherin) is a

component of the AJ, it has seven ECdomains, instead of the five in the vertebrateclassic cadherins (Oda et al. 1994). The otherDrosophila classic cadherin, DN-cadherin,has even 17 EC domains (Iwai et al. 1997).These Drosophila cadherins also contain otherdomains, such as EGF-like and lamininglobular-like domains, inserted between theset of EC domains and the transmembranedomain. As a result, these Drosophila cadherinsare much larger in size than the vertebrate ones,despite the similar appearance of their AJs. Thefunctional importance of AJs also differs amongspecies. For example, Caenorhabditis elegans hasa classic-cadherin-type molecule (HMR-1), butits role in cell junction formation is limited:HMR-1-deficient animals fail to enclose theepidermal sheets, but their general cell junc-tions look normal even in the absence of thiscadherin (Cox et al. 2004). The organizationof apical junctional complexes is also differentbetween vertebrates and invertebrates. In Dro-sophila, the relative positions of the AJ andtight junction are inverse; that is, the AJ is

F-actin

Afadin

Nectin Cadherin

p120catenin

PLEKHA7

Nezha

–

Microtubule

+

EPLIN

a-catenin

b-catenin

Figure 2. Representative molecular constituents of the zonula adherens. These constituents vary with the types ofadherens junction.

Adherens Junction

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located above the septate junction, which isconsidered as a structure equivalent to thevertebrate tight junction. Irrespective of thesespecies-dependent diversifications, the keystructure and function of the cadherin cyto-plasmic domain is highly conserved amongdifferent species; that is, the classic cadherinsfrom any species interact with their conservedcytoplasmic partners (see the following).

After the discovery of the classic cadherins,a number of other molecules that share theconserved EC domains but have divergent cyto-plasmic sequences were identified, and these arecollectively called nonclassic cadherins. Theseinclude desmosomal cadherins (Wheeler et al.1991; Buxton and Magee 1992), protocadherins(Redies et al. 2005; Morishita and Yagi 2007),Fat and Dachsous cadherins (Saburi andMcNeill 2005; Tanoue and Takeichi 2005), andFlamingo/Celsr (Takeichi 2007) (see McNeillet al. 2009). Among them, desmosomal cadher-ins are the closest to the classic cadherins, anddesmosomes, in fact, are similar in appearanceto AJs, though not identical from a number ofaspects (Holthofer et al. 2007) (see Greenet al. 2009; Delva et al. 2009). Except for thedesmosomal cadherins, other nonclassic cad-herins appear not to organize specialized junc-tions, nor to be the components essential forAJ formation; although, they generally canundergo homophilic interactions at the cell–cell interfaces. These nonclassic cadherins seemto have acquired unique molecular roles, ratherthan that for the physical linking of cells. Forexample, some of the protocadherins negativelyregulate the classic cadherin-dependent adhesion(Chen and Gumbiner 2006), and Fat (Nolletet al. 2000; Strutt and Strutt 2005; Tanoue andTakeichi 2005) and Flamingo (Usui et al. 1999)regulate planar cellular polarity as well as otherforms of cellular interactions.

CADHERIN–CATENIN COMPLEX

The cytoplasmic domains are highly conservedamong the classic cadherin members, and theybind common cytoplasmic molecules, collec-tively called catenins (Fig. 2). The juxtamem-brane portion of the cytoplasmic domain

associates with p120-catenin, which belongsto a subfamily of the armadillo proteins(Reynolds et al. 1992; Shibamoto et al. 1995;Hatzfeld 2005). The carboxy-terminal half ofthe cytoplasmic domain, on the other hand,binds b-catenin or plakoglobin (g-catenin),which are close relatives of each other (Ozawaet al. 1989; Knudsen and Wheelock 1992; Ozawaand Kemler 1992). As mentioned above, thesemolecular partners for the cytoplasmic domainare well conserved among different animalspecies; e.g., its invertebrate versions can bindboth p120-catenin (JAC-1 in C. elegans) andb-catenin (Armadillo in Drosophila; HMP-2in C. elegans) (Peifer and Wieschaus 1990; Coxet al. 2004). These catenins in turn associatewith a variety of other molecules, includingcytoskeletal proteins and their regulators.These cytoplasmic components of AJ affectthe adhesive action of the extracellular domainof cadherins in various ways, leading to alter-ations in the strength and stability of cell–cellcontacts.

INTERACTIONS WITH THE ACTINCYTOSKELETON

The AJ is morphologically associated withactin filaments, posing the questions of howthis association is established and what rolethe actin plays in AJ organization and function.A key player is thought to be a-catenin, a mol-ecule similar to vinculin (Herrenknecht et al.1991; Nagafuchi et al. 1991). The a-cateninbinds b-catenin, resulting in the formationof the cadherin–b-catenin–a-catenin com-plex. Early biochemical studies showed thata-catenin can interact with actin filaments(Rimm et al. 1995), giving rise to the generalbelief that a-catenin acts as a linker betweenthe cadherin–b-catenin complex and F-actin.However, this concept was challenged by thefinding that the a-catenin complexed withcadherin and b-catenin cannot bind F-actinin vitro and that only free a-catenins cando so (Drees et al. 2005; Yamada et al. 2005).This finding suggested the possibility thatthe cadherin–b-catenin–a-catenin complexmight interact with F-actin via some other





mediator(s). In fact, a-catenin has been shownto associate with actin-binding proteins such asformin (Kobielak et al. 2004) and vinculin(Watabe-Uchida et al. 1998), and a very recentstudy identified another actin-binding protein,EPLIN (epithelial protein lost in neoplasm; alsoknown as Lima-1), as ana-catenin partner (Abeand Takeichi 2008). EPLIN is known to enhancethe bundling of actin filaments and to stabilizethem by suppressing F-actin depolymerization(Maul et al. 2003). The EPLIN can binda-catenin when the latter is associated withthe cadherin–b-catenin complex, and thisentire complex binds F-actin. This findingillustrates a novel pathway for the interactionbetween cadherin and F-actin (Fig. 2).

It should be noted that the morphology ofactin-AJ association differs with the cell typesor cellular conditions (Yonemura et al. 1995).Although actin filaments run parallel alongthe ZA in simple cuboidal or columnar epi-thelia, these filaments often perpendicularlyterminate at cell–cell borders in many otherjunctions, e.g., in those of stratified epithelium-derived cells and fibroblastic cells, and also inimmature junctions of most cell types (Fig. 1).It is highly possible that different molecularmechanisms operate for the linking of F-actinto AJs in such different types of junction. Infact, even in the absence of EPLIN, F-actin stillmorphologically associates with AJs (see thefollowing). Meanwhile, the actin-associatedcadherins do not necessarily form a staticdomain. In some cell lines, actin filaments arealigned from the basal to apical end of celljunctions, and these actins display a type of ret-rograde flow. Cadherins are tethered to theseactin filaments in an a-catenin-dependentmanner and move together with the actins,displaying “cadherin flow” (Kametani andTakeichi 2007); although, the biological role ofthis flow is not understood yet. In matureepithelia, a-catenin is also important for regu-lating the mobility of cadherins (Cavey et al.2008) (see Stepniak et al. 2009).

What happens if the linkage between thecadherin–catenin complex and F-actin is dis-rupted? When a-catenin is removed, AJ orga-nization is disrupted, and the apical actin

belt becomes segregated from the cadherin–catenin complex (Watabe-Uchida et al. 1998).If this occurs in neural epithelia in vivo, theirarchitecture is seriously damaged (Vasioukhinet al. 2001). Removal of neural a-catenin(aN-catenin) from synaptic AJs destabilizessynaptic contacts (Abe et al. 2004). On theother hand, EPLIN loss in epithelia results indifferent types of defects at the junctions. Thecircumferential actin belt disappears, beingconverted to radially oriented actin filaments,indicating that EPLIN is important not onlyfor the linkage between cadherin and F-actinbut also for stabilizing this unique configura-tion of actin fibers (Abe and Takeichi 2008).Importantly, the actin filaments, rearranged asa result of EPLIN loss, still target cadherins,which now assume a spotty localization asseen in fibroblasts or immature epithelial junc-tions. This finding suggests that EPLIN is notthe sole linker between cadherin and F-actinand that other linkers must be present andalso suggests the possibility that the shape ofAJs could be altered by the type of cadherin–actin linkers.

Because the actin filaments are essential forAJ assembly, regulators of these filaments wouldbe expected to affect it. In fact, Rho-family smallGTPases, such as RhoA, Rac1, and Cdc42, aswell as their GEFs and GAPs, have been shownto regulate AJ formation and integrity (Braga2000). Because these molecules are used for awide variety of cell behavior, precise dissectionof whether a given GTPase targets the actin fila-ments directly involved in junction formationor those involved in other processes, such ascell motility, is important for our correct under-standing of the roles of these enzymes. aPKC hasalso been shown to be essential for the circum-ferential actin belt formation in epithelial cells.When aPKC is inactivated, the circumferentialactin belt is lost, and AJs become spot-like(Suzuki et al. 2002). In vivo, aPKC knockoutresults in the loss of adherens junctions inneuroepithelial cells (Imai et al. 2006). It hasbeen proposed that the action of aPKC is toantagonize the myosin-II-driven centripetalcontraction of the circumferential actin cables(Kishikawa et al. 2008).

Adherens Junction




The contractility of AJ-associated circum-ferential actin belts is used for morphogene-sis. A well-known example is the Shroom3-dependent constriction of the zonula adherens(ZA) in epithelial layers, where constrictionplays an important role in epithelial folding orbending (Haigo et al. 2003; Hildebrand2005). In this case, the actin-binding proteinShroom3 recruits Rho kinases (ROCKs) nearthe ZA, and activates myosin-II, inducingthe contraction of the circumferential actinbelts (Nishimura and Takeichi 2008). Theactomyosin-dependent regulation of the AJ isalso implicated in cell intercalation duringearly morphogenesis of Drosophila embryos(Bertet et al. 2004; Zallen and Wieschaus2004; Blankenship et al. 2006).

INTERACTIONS WITH MICROTUBULES

As compared with the actin cytoskeleton, lessattention has been paid to microtubules(MTs) with reference to the structure and func-tion of the AJ. Actually, the MTs do not showspecialized condensation at the AJ, contrastedwith the unique bundling of actin fibers alongthe AJ. However, MTs have occasionally beenobserved to be located in a close proximityto the AJ, running parallel to this junction.Moreover, the radially extending MTs aretargeted to the AJs with their plus ends in aCLIP-170-dependent manner, and blocking ofthe MT extension toward the AJs causes areduction in the accumulation of junctionalE-cadherin (Stehbens et al. 2006). In addition,dynein was found to bind b-catenin, and thisb-catenin-associated dynein was proposed totether MTs to cell junctions (Ligon et al. 2001;Shaw et al. 2007). These observations suggest apotential interaction of AJ with MT plus ends,and their interaction seems to have some rolesin AJ assembly. In support of this idea, reagentsthat depolymerize MTs are known to disruptthe integrity of the AJs (Waterman-Storeret al. 2000), and even inhibit the disassemblyof cell junctions (Ivanov et al. 2006)

Recent studies have also revealed that MTminus ends interact with AJs via p120-catenin(p120). This catenin recognizes and binds a

specific sequence located in the juxtamembraneregion of the cadherin cytoplasmic domain. Thep120-cadherin binding is known to play acentral role in the stability of cadherin-mediatedjunctions; i.e., when p120 is removed, the plasmamembrane-associated cadherins become endo-cytosed, leading to reduced cell–cell associ-ations (see the following discussion). Thisaction of p120 requires the armadillo domainoccupying its central region (Liu et al. 2007).Other series of studies have found that p120can associate with MTs (Chen et al. 2003;Roczniak-Ferguson and Reynolds 2003; Franzand Ridley 2004; Yanagisawa et al. 2004), andthis ability of p120 requires its carboxy-terminaldomain (Ichii and Takeichi 2007), suggest-ing that the amino-terminal and armadillodomains of this catenin have separate functions.Further studies on the amino-terminal domainidentified a new partner for p120 (Meng et al.2008). This is PLEKHA7, which binds theamino-terminal domain of p120. Intriguingly,this protein localizes specifically along the ZA,but not in other portions of the junctions inepithelial sheets, despite the ubiquitous distri-bution of p120 and cadherins at the cell–cellcontacts. Depletion of PLEKHA7 exclusivelydisrupts the ZA, but not the entire cell–celljunctions, suggesting that this protein isspecifically required to maintain the ZA.Subsequently, PLEKHA7 was found to bindanother protein, termed Nezha, which is againdistributed along the ZA; although Nezha wasalso detected as punctate signals in the cyto-plasm. Nezha displays an important property:It binds the minus ends of MTs, and tethersthem to the ZA, allowing their extension andretraction from the cell junctions.

These studies have uncovered the presenceof a novel population of MTs, whose minusends are anchored at the ZA via thePLEKHA7–Nezha complex (Fig. 2). The func-tions of these MTs are not fully understoodyet, but preliminary observations suggest thatminus-end directed kinesin motors, such asKIFC3, use these MTs to transport themselvesto the ZA. Depletion of PLEKHA7, Nezha,KIFC3, and MTs results in similar defectsin ZA organization. Thus, these molecules





appear to work together by forming a complexto sustain the ZA architecture. It shouldbe re-emphasized that this novel molecularcomplex appears to be important only for theZA, but not for the entire cadherin-mediatedcell–cell contacts, confirming that the ZA is aspecialized domain of the cadherin-mediatedjunctions/AJs. The mechanisms of howPLEKHA7 interacts with p120 only at the ZAremains unknown.

In sum, evidence is accumulating that MTsplay roles in AJ assembly, where both the plusand minus ends of MTs have been suggestedto be involved. Although the molecular mech-anisms for the plus-end interactions with AJshave not been determined yet, the two popu-lations of MTs with the opposite polaritymight cooperate together for AJ regulation.

COOPERATION BETWEEN CADHERINAND NECTIN

Nectins are a family of immunoglobulin-like molecules, consisting of four members(Nakanishi and Takai 2004). They are accumu-lated at the AJ, colocalizing with cadherins(Fig. 2). The cytoplasmic domain of nectinsassociates with AF6/afadin via the carboxy-terminal PDZ-binding motif of the former.Afadin, on the other hand, was shown to inter-act with a-catenin, suggesting that a physicalassociation might occur between the cad-herin–catenin and nectin–afadin complexes(Tachibana et al. 2000). Because afadin is anactin-binding protein (Mandai et al. 1997;Takahashi et al. 1999), this system may alsoplay a role in the linking of AJ to actin filaments.

Nectins interact with other nectins in eithera homophilic or heterophilic way. Differentfrom the classic cadherins, nectins preferheterotypic partners to homotypic ones, andtheir heterophilic binding produces strongercell–cell adhesion than the homophilic inter-actions (Fabre et al. 2002; Yasumi et al. 2003;Martinez-Rico et al. 2005). Importantly,during the process of early cell–cell contacts,nectins first accumulate at the contacts, andthen cadherins follow them (Takai et al. 2003),suggesting that the former may guide the

latter in their junctional localization. This canbe seen in the following example: When cellsexpressing nectin-1 and nectin-3 are mixed,these nectins preferentially accumulate at theheterotypic interfaces of the cells. In thesecells, cadherins also become predominantlyconcentrated at the heterotypic nectin-positivecell boundaries (Togashi et al. 2006). Thus,this form of nectin interaction serves forrecruiting cadherins to heterotypic cell–cellborders, which are otherwise distributedthroughout cell–cell borders. This ability ofnectins is used for recruiting cadherins to thesynaptic contacts formed between two distinctdomains of hippocampal neurons, i.e., axonsand dendrites, which express nectin-1 andnectin-3, respectively (Togashi et al. 2006).Thus, nectins show important cooperativitywith classic cadherins in generating heterotypiccell–cell contacts.

INTERACTIONS WITH CELL POLARITYREGULATORS

How is the apical junctional complex locatedapically? The apico-basal polarity of cells isregulated by a couple of molecular complexes,including the aPKC-Par6-Par3 complex local-ized at a subapical region of the cell junction(Margolis and Borg 2005). Genetic analysisusing Drosophila embryos showed that theDrosophila homolog of Par3 (Bazooka) couldestablish apical complexes in the absence ofAJs, indicating that Bazooka acts upstream ofAJ formation (Harris and Peifer 2005). Somereports, on the other hand, suggest the AJshave a physical interaction with these polarityfactors: Par3 and Par6, but not aPKC, coprecipi-tate with VE-cadherin, the endothelial-specificcadherin (Iden et al. 2006). Par3/Bazooka colo-calizes with cadherins in epithelial junctions(Harris and Peifer 2005; Afonso and Henrique2006). These observations illustrate a possiblepathway by which the apical membrane domainis primarily determined by those apical deter-minants, and, in turn, the AJ/ZA is recruitedto this domain, possibly via interactions withthe pre-existing Par complex. Cadherins mayalso interact with another polarity regulator,

Adherens Junction




the Scrib-Dlg-Lgl complex localized at thelateral membrane (Reuver and Garner 1998;Navarro et al. 2005). However, the mechanismsresponsible for the clustering of the threejunctions, i.e., tight junction, AJ, and desmo-somes, to form the apical junctional complexand their alignment in a specific order remainunresolved.

CADHERIN EXPRESSION AND RECYCLING

The AJ in mature tissues appears to be a staticstructure, but actually, cadherin molecules areturning over, and their surface levels are con-trolled by various mechanisms. Elucidatingthese mechanisms is important for a molecularunderstanding of the homeostatic nature ofcell junctions. In epithelial cells, the newlysynthesized cadherins are transferred from theGolgi to AJs via an exocyst-dependent mech-anism (Yeaman et al. 2004). For recycling,E-cadherin is transported to recycling endo-somes, and then trafficked to late endosomesfor return to the cell surface. DE-cadherin traf-ficking depends on the interaction of Rab11 andb-catenin with exocyst components Sec15 andSec10, respectively (Langevin et al. 2005).

The cell surface-located cadherins are sta-bilized by their homophilic interactions. Whencell–cell junctions are artificially disrupted bydepletion of extracellular calcium or by othermeans, the cadherins are actively internalized(Kartenbeck et al. 1991). Under the physio-logical situation, p120 plays a critical role incadherin stability (Reynolds 2007). It has beenproposed that the attachment of p120 to cad-herin masks a dileucine motif on the juxta-membrane region of the cytoplasmic domain,which is sensitive to endocytotic signals(Miyashita and Ozawa 2007), and therebystabilizes the cadherins. The p120-cadherinbinding is strengthened by the interaction ofp120 with nectin-associated afadin in a waydepending on Rap1, a small GTPase knownto be important for AJ formation (Kooistraet al. 2007), and this results in the suppressionof E-cadherin endocytosis (Hoshino et al.2005). A component of the tight junc-tion, PALS1, can also regulate the cadherin

trafficking: In PALS1-knocked-down epithelialcells, the exocyst complex is mislocalized, andE-cadherin puncta accumulate in the cell per-iphery (Wang et al. 2007). Recently, theCdc42-Par6-aPKC pathway was reported tostabilize the AJ via the control of Arp2/3-dependent endocytosis (Georgiou et al.2008; Leibfried et al. 2008). Thus, the cadherinstability is regulated in a variety of ways.

The level of cadherins on the cell surface isalso controlled by transcriptional and posttran-scriptional regulators. Many zinc finger familytranscription factors have been implicatedin the control of cadherin expression. Forexample, the zinc finger transcription factor“Snail” is considered as a repressor ofE-cadherin transcription, and the expressionof Snail inversely correlates with that ofE-cadherin (Cano et al. 2000). Other zinc-finger-family transcription factors, such asSIP1, dEF1, Slug, Twist, and E12, similarly actas cadherin transcription repressors throughtheir interaction with the E-box (Remacleet al. 1999; Comijn et al. 2001; Perez-Morenoet al. 2001; Hajra et al. 2002; Yang et al. 2004).Recently, a family of micro RNAs (miRNAs),such as miR-200, was reported to control theexpression level of E-cadherin during theepithelial–mesenchymal transition (EMT).Ectopic expression of miR-200 in cell lines up-regulates the expression of E-cadherin. ThesemicroRNAs act on E-cadherin transcriptionalrepressors ZEB1/dEF1 and ZEB2/SIP1, andthereby regulate EMT (Gregory et al. 2008;Park et al. 2008). Another miRNA, miR-373,was found to induce E-cadherin expression byrecognizing a target site in the promoter of thegene for E-cadherin (Li et al. 2006; Place et al.2008). These findings provide novel insightsinto the regulation of cadherin gene expression,which shows highly complex patterns duringdevelopment (Takeichi 1988).

CONCLUDING REMARKS

The AJs do not display highly specialized ultra-structures, except for having the actin under-coats, as compared with the tight junction,desmosome, and gap junction, each of which





shows uniquely decorated plasma membranesor intercellular architecture. The relatively sim-ple structure of the AJ may reflect its dynamicnature and flexibility. In fact, the overall mor-phology of AJs varies with the cell type andchanges during morphogenetic cell rearrange-ments such as convergent-extension and EMT.The observations of AJ remodeling duringDrosophila germ band extension suggest thatthe AJs function not only as a physical ligandbetween cells but also as an active regulator forcell rearrangement (Lecuit and Lenne 2007).Under these circumstances, studies on AJs willcontinue for answering at least two lines ofquestions: How are the AJs maintained or dis-rupted? And, how does the regulation of AJscontribute to normal morphogenetic cell be-havior as well as to the pathogenic one, suchas cancer invasion and metastasis?

The integrity of AJs is sustained by cyto-plasmic components, including catenins andassociated molecules, actin filaments, and micro-tubules, as well as by the recycling machinery.Although the entire system is apparently com-plicated, one of the crucial mechanisms tomaintain the AJs obviously underlies theinterplay of cadherin and the cytoskeleton. Wehave not obtained a complete answer to thelong-standing question of how actin regulatesthe adhesive function of cadherins. Now, anew question has been posed: What role doMTs have in AJ assembly? Future studies areneeded to resolve these problems, through theanalysis of the roles of actin regulators andMT-associated proteins.

To understand the morphogenetic roles ofAJs, physical and mathematical modeling isbecoming a powerful tool (Honda et al. 2008).For example, anisotropy of cortical tension atthe AJs has been shown to be sufficient todrive tissue elongation (Rauzi et al. 2008). Onthe experimental biology side, it will be impor-tant to delineate the cooperative mechanismsbetween AJs and other morphogenetic regu-lators that work at cell–cell borders, forexample, planar cell polarity (PCP) signaling(Fanto and McNeill 2004), as AJs alone wouldnot be sufficient for responding to so manymorphogenetic signals.

Other important issues yet unansweredinclude how the morphology of AJs differsbetween cell types, and the roles of differentclassic cadherin members in AJ formation.Each cadherin subtype, which shows a uniquetissue distribution, might confer some kind oftissue specificity on the structure and functionsof AJs, but this concept has not been tested. Theroles of nonclassic cadherins in AJ regulationis another interesting issue, as some proto-cadherins can down-regulate the functions ofclassic cadherins (Chen and Gumbiner 2006;Nakao et al. 2008). There must be a number ofunknown interactions between the classic andnonclassic cadherin systems, as both of theircomponents accumulate at cell–cell contacts.All these studies targeted on the AJ give usdeeper insights into the problem of howindividual cells, which can freely move whenisolated, can regulate themselves via cell–cellcontacts to generate highly ordered multi-cellular systems.

ACKNOWLEDGMENTS

We thank Katsutoshi Taguchi for photographs.Work in our laboratory was supported by theprogram Grants-in-Aid for Specially PromotedResearch of the Ministry of Education, Science,Sports, and Culture of Japan.

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Adherens Junction




August 5, 20092009; doi: 10.1101/cshperspect.a002899 originally published onlineCold Spring Harb Perspect Biol

Wenxiang Meng and Masatoshi Takeichi Adherens Junction: Molecular Architecture and Regulation

Subject Collection Cell-Cell Junctions

Adherens Junctions, and Vascular DiseaseVascular Endothelial (VE)-Cadherin, Endothelial

Costanza GiampietroMaria Grazia Lampugnani, Elisabetta Dejana and and Networks

Junctions: Protein Interactions Building Control Cell−Signaling by Small GTPases at Cell

Vania Braga

An Evolutionary PerspectiveOrchestrate Tissue Morphogenesis and Function:Coordinate Mechanics and Signaling to Adherens Junctions and Desmosomes

Wickström, et al.Matthias Rübsam, Joshua A. Broussard, Sara A.

Cell Junctions−Receptors at Nonneural Cell Making Connections: Guidance Cues and

KennedyIan V. Beamish, Lindsay Hinck and Timothy E.

SignalingCell Contact and Receptor Tyrosine Kinase−Cell

McClatcheyChristine Chiasson-MacKenzie and Andrea I.

AssemblyThe Cadherin Superfamily in Neural Circuit

James D. Jontes

Junctions in AngiogenesisCell−Endothelial Cell−−Hold Me, but Not Too Tight

Anna Szymborska and Holger GerhardtCell Junctions−Cell

Mechanosensing and Mechanotransduction at

Alpha S. Yap, Kinga Duszyc and Virgile ViasnoffConnexins and Disease

al.Mario Delmar, Dale W. Laird, Christian C. Naus, et Cadherins for Hearing and Balance

Cell Adhesion: Sensational−Beyond Cell

Araya-Secchi, et al.Avinash Jaiganesh, Yoshie Narui, Raul

Cell Junctions in Hippo SignalingRuchan Karaman and Georg Halder Signaling Networks

Cell Junctions Organize Structural and−Cell

ChavezMiguel A. Garcia, W. James Nelson and Natalie

and the Development and Progression of CancerCell Adhesion−Loss of E-Cadherin-Dependent Cell

Heather C. Bruner and Patrick W.B. Derksenand Mucosal DiseaseCell Biology of Tight Junction Barrier Regulation

Aaron Buckley and Jerrold R. Turner

Consequences for Tissue MechanicsDesmosomes and Intermediate Filaments: Their

MaginMechthild Hatzfeld, René Keil and Thomas M.

JunctionsAdherensCytoskeleton at Integration of Cadherin Adhesion and

René Marc Mège and Noboru Ishiyama

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Adherens Junction: Molecular Architecture and …cshperspectives.cshlp.org/content/1/6/a002899.full.pdfAdherens Junction: Molecular Architecture and Regulation Wenxiang Meng and Masatoshi