α-catenin: at the junction of intercellular adhesion and actin dynamics

614 | AUGUST 2004 | VOLUME 5 www.nature.com/reviews/molcellbio

R E V I E W S

In multicellular organisms, cell–cell contacts that aremediated by CLASSIC CADHERINS are essential in manyfundamental processes, including morphogenesis,maintenance of tissue integrity, wound healing andcell polarity. The prototype classic cadherin is thetransmembrane protein E-cadherin. This protein usesits extracellular domain to bind Ca2+ and interact withE-cadherin on adjacent cells, thereby formingADHERENS JUNCTIONS. To establish efficient cell–cell junc-tions, E-cadherin uses its cytoplasmic domain to coupleto catenins and the actin cytoskeleton. This associationsets the classic cadherins apart form DESMOSOMAL cad-herins, which form complexes with the intracellularproteins plakoglobin and desmoplakin to form amore robust Ca2+-induced adhesive interaction — thedesmosome — that links the INTERMEDIATE-FILAMENT

cytoskeleton (see also the article by Lynne Chang andRobert Goldman in this issue). Many cells have bothadherens junctions and desmosomes, which functioncoordinately in intercellular adhesion (FIG. 1).

Desmosomes use their attachments to intermediatefilaments to provide mechanical strength to intercel-lular connections1–3. They are particularly importantin tissues that are subjected to substantial physical stress,such as muscle and epidermis. By contrast, adherensjunctions use their connections to the ACTOMYOSIN

NETWORK to remodel cell–cell interactions and provide

flexible dynamic adhesion during wound repair ofadult tissues and embryonic development4–6. Whereasdesmosomes and their associated intermediate filamentsfunction as molecular clamps to reinforce intercellularjunctions, actin dynamics and adherens-junction for-mation have been implicated in the initial steps ofbringing membranes together and in the final stepsof sealing membranes into epithelial sheets.

Dysregulation of cadherin-mediated junctions canlead to severe developmental defects. Mutations indesmosomal genes often result in degenerative disor-ders, and several excellent reviews have recentlydescribed the composition and function of these robustadhesive structures1–3. Curiously, however, althoughmutations in adherens-junction proteins can sometimescause tissue degeneration, in other cases they can con-tribute to carcinogenesis and metastasis4–6. With anincreasing knowledge of the composition of adherensjunctions, their assembly, and their relationship to othermembrane junctions and receptors, new insights intosome of these processes are beginning to unfold.

At the heart of the story lie the catenins, whichassociate with the cytoplasmic domain of cadherins toassemble a protein complex that can associate with theactin cytoskeleton, coordinate stable intercellularadhesion, and regulate indirect associations withdesmosomes, TIGHT JUNCTIONS, growth-factor receptors

α-CATENIN: AT THE JUNCTION OFINTERCELLULAR ADHESION ANDACTIN DYNAMICSAgnieszka Kobielak and Elaine Fuchs

α-catenin has often been considered to be a non-regulatory intercellular adhesion protein, incontrast to β-catenin, which has well-documented dual roles in cell–cell adhesion and signaltransduction. Recently, however, α-catenin has been found to be important not only inconnecting the E-cadherin–β-catenin complex to the actin cytoskeleton, but also in coordinatingactin dynamics and inversely correlating cell adhesion with proliferation. As the number of α-catenin-interacting partners increases, intriguing new connections imply even more complexregulatory functions for this protein.

CLASSIC CADHERINS

Cadherins are transmembranemolecules that mediate Ca2+-dependent cell–celladhesion. Classic cadherins aretypified by an extracellularsegment that consists of fivedistinct Ca2+-binding domainsand a conserved cytoplasmicdomain, which binds β-catenin.The extracellular part interactshomotypically with cadherinson the surface of neighbouringcells to form adherens junctions.The cytoplasmic tail links theactin cytoskeleton to adherensjunctions.

Howard Hughes MedicalInstitute, Laboratory ofMammalian Cell Biologyand Development,Rockefeller University,1230 York Avenue, Box 300,New York, New York 10021,USA. Correspondence to E.F.e-mail:[email protected]:10.1038/nrm1433

F O C U S O N C Y T O S K E L E T A L D Y N A M I C S

NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 5 | AUGUST 2004 | 615

for α-catenin have surfaced, which have shed new lighton the functions of α-catenin and its underlying mech-anisms of action (FIG. 2).

α-catenins in development and differentiationα-catenin is conserved across the eukaryotic kingdom,where it functions broadly in intercellular adhesion dur-ing development and differentiation. In Drosophilamelanogaster, cell adhesion is disrupted when α-catenincontains a mutation in the binding site for Armadillo,which is the D. melanogastor homologue of β-catenin22.Adherens junctions are also present in the nematodeCaenorhabditis elegans, which expresses the homologuesHMR-1 (cadherin), HMP-1 (α-catenin) and HMP-2(β-catenin)23.

In mice, there are three α-catenins and one close rela-tive, which all share substantial amino-acid sequenceidentity (TABLE 1): αE-catenin is most prevalent in epithe-lial tissues24; αN-catenin is restricted to neural tissues25,26;αT-catenin is expressed primarily in heart tissue27; andα-catulin, which is an α-catenin-like protein, is ubiqui-tously expressed28,29. A more distant relative is vinculin,which is ubiquitously expressed and localizes to bothFOCAL ADHESIONS and adherens junctions30 (TABLE 2).

αE-catenin. Formerly known as cadherin-associatedprotein (CAP)-102, αE-catenin is the founding memberof the α-catenin family31,32. Localized on chromosome18q11.0 (REF. 33), the murine gene encodes the 102-kDaαE-catenin32,34. The human αE-catenin gene(CTNNA1) localizes to chromosome 5q31 and consistsof 16 coding exons (906 amino acids; 102 kDa) and atleast one 5′ non-coding exon35. Human and mouse αE-catenin proteins are exceptionally highly conserved,sharing 99.2% identity. This evolutionary conservationmight reflect the diversity of the interacting proteinpartners and functions of αE-catenin36.

αE-catenin was initially identified on the basis of itsability to associate with E-cadherin24,34. It also interactswith other classic cadherins, such as neuronal (N) andplacental (P) cadherin24. When kidney epithelial cells arecultured in medium that contains Ca2+ at levels thatinduce the formation of adherens junctions, E-cadherinand catenins shift from the soluble to the cytoskeletalfraction (if the cells are lysed and fractionated) con-comitant with the formation of stable adherens junc-tions37,38. Gene-targeting studies in mice indicate thatαE-catenin is required to mediate the formation ofadherens junctions in epithelial cells18,34,39. In addition,cancer cell lines that lack αE-catenin do not show propercell–cell adhesion10 unless the wild-type gene is reintro-duced and adherens-junction formation is restored14,25,40.

A GENE-TRAP-induced mouse mutation of the αE-catenin gene, which specifically deletes the region thatencodes the carboxy-terminal third of the protein,results in an embryonic-lethal phenotype that is similarto that of the E-cadherin-null-mutant mouse41. In bothcases, the proteins are required at the BLASTOCYST STAGE

and, without αE-catenin, the outer epithelial covering(trophectoderm) of the developing embryo lacksintegrity41,42.

and microtubules4. In addition, in response to WNTsignalling, excess β-catenin that is not used in cell–celljunctions can accumulate and adopt a second func-tion as a nuclear transcriptional co-activator for thelymphoid enhancer-binding factor-1 (LEF1)/T-cell-specific factor (TCF) family of DNA-binding pro-teins7–9. As sustained stabilization of β-catenin hasbeen associated with a range of human cancers, thisregulatory function has been the main focus of thecancer–cadherin link. The reader is referred to severalelegant reviews that have covered, in depth, the role ofβ-catenin in signalling and cancer7–9. However, muta-tions in E-cadherin and α-catenin can also contributeto cancers10–17, and gene-targeting studies indicatethat the proliferation that is sometimes associatedwith such mutations does not always result from theactivity of nuclear β-catenin18,19.

In this review, we focus on α-catenin, which is theprotein that connects E-cadherin–β-catenin complexeswith the actin cytoskeleton20,21. Whereas all othercatenins (β-catenin, plakoglobin and p120 catenin)share considerable sequence similarity and belong tothe Armadillo family of proteins, α-catenin differsnotably in both sequence and structural organization.Although it was previously considered to be solely astructural protein, new roles have begun to emerge forα-catenin in both assembling the cytoskeleton and reg-ulating its dynamics at cell–cell junctions. In addition,recent studies imply that the interactions of α-cateninwith E-cadherin–β-catenin complexes might controlthe accessibility of these complexes to other cellularproteins. In the past few years, various binding partners

ADHERENS JUNCTION

A specialized intercellularjunction of the plasmamembrane, in which thecadherin molecules of adjacentcells interact in a Ca2+-dependent manner. Actinfilaments are linked to thisstructure through catenins thatare located underneath thejunction.

DESMOSOMES

Specialized junctional structuresthat form a tight connectionbetween epithelial cells orcardiac myocytes. They consistof several transmembraneadhesive glycoproteins(desmogleins and desmocollins)and cytoplasmic plaque proteins(desmoplakins) that link tointermediate filaments.

INTERMEDIATE FILAMENTS

Proteins that acquired theirname from the diameter of theirpolymeric structure, which ismidway between the diametersof thin actin microfilaments andthick microtubules. Their abilityto form very stable filamentsenables them to confermechanical strength on thecytoskeleton.

Figure 1 | Intercellular junctions in skin. The electron micrograph and correspondingschematic depict the main types of intercellular junction in epithelial cells. Tight junctions arecomposed of transmembrane proteins that link to the actin cytoskeleton and prevent the leakageof small molecules through intercellular spaces. Adherens junctions are formed by homophilicinteractions between E-cadherin molecules, and are connected to the actin network through β- and α-catenins. They function to coordinate the actin cytoskeleton across an epithelial sheet.Desmosomes are composed of desmosomal cadherins that are linked to intermediate filamentsand integrate the intermediate-filament network across the epithelial sheet. Electron micrographcourtesy of H. Amalia Pasolli, Rockefeller University, New York, USA.

Tight junction

Desmosome

Adherens junction

F-actin E-cadherin

Desmosomal cadherin

Intermediate filament

Transmembrane proteins


R E V I E W S

that lead to uncontrolled growth. In the mice that lackedαE-catenin, however, the skin epithelium uniformlyshowed epidermal hyperproliferation shortly afterαE-catenin-gene ablation, which prompted researchersto investigate alternative molecular explanations. In vitroand in vivo studies uncovered a sustained activation of theRas–ERK/MAPK (extracellular signal-regulatedkinase/mitogen-activated protein kinase) pathway, whichseemed to involve the insulin–insulin-like-growth-factorsignal-transduction pathway18. Curiously, these perturba-tions seemed to occur independently of the effects onintercellular adhesion and of β-catenin–LEF1/TCF-mediated gene transcription.Although the precise mech-anism remains elusive, these findings indicate thatwhen αE-catenin is absent, E-cadherin–β-catenin com-plexes might interact in new ways with components ofsignal-transduction pathways that are involved in cell-cycle regulation. Such a mechanism could be importantfor understanding the inverse link between αE-cateninmutations and tumorigenesis. In a ‘natural’ setting, themechanism might be relevant to processes such as woundhealing, in which proliferation is transiently enhancedand cell–cell adhesion is reduced during the epithelial

To examine the functional importance of αE-cateninin other epithelial tissues, Vasioukhin and colleaguesengineered a conditional αE-catenin-mutant mouse18.When αE-catenin expression was ablated from thedeveloping skin around embryonic day 15, hair-follicledevelopment was impaired and the architecture of theepidermal tissue was markedly altered. In the epider-mis, the formation of adherens junctions seemed to becompromised, even though E-cadherin and β-catenincomplexes still localized to cell–cell borders. Desmosomesloosely held the skin epithelium together, but partialdefects in epithelial polarity arose, including suprabasalmitoses (mitosis is usually observed only in the basal layerof the epidermis). Perhaps most intriguing was the pres-ence of epidermal hyperproliferation and multinucleatecells, which were accompanied by epithelial invaginationsthat resembled the precancerous lesions that are knownas squamous-cell carcinomas in situ.

Although null mutations in αE-catenin have beenassociated with epithelial cancers10–14, it has usually beenassumed that perturbations in cell–cell adhesion are late,rather than early, steps in carcinogenesis, and that theyare preceded by mutations in cell-cycle-regulated genes

ACTOMYOSIN NETWORK

A complex of myosin and actinfilaments that is responsible for arange of cellular movements ineukaryotic cells. Myosins cantranslocate vesicles or othercargo on actin filaments.

TIGHT JUNCTIONS

The most apical intercellularjunctions, which function asselective (semi-permeable)diffusion barriers betweenindividual cells. They areidentified as a belt-like region inwhich two lipid-apposingmembranes lie close together.

FOCAL ADHESIONS

A cell-to-substrate adhesionstructure that anchors the endsof actin microfilaments (stressfibres) and mediates strongattachment to substrates.

GENE TRAP

A methodology that is used tocharacterize new genes andanalyse their importance inbiological phenomena. Thetechnique involves the use ofmouse embryonic stem cells andreporter vectors that aredesigned to randomly integrateinto the genome, tag an insertionsite and generate a mutation.

BLASTOCYST STAGE

The stage during embryonicdevelopment that ischaracterized by the formationof two cell types: theembryoblast (the inner cell masson the inside of the blastocoel)and the trophoblast (the cells onthe outside of the blastocoel).

Figure 2 | A multiprotein complex at adherensjunctions. The extracellular region of E-cadherin, whichcontains extracellular cadherin (EC) domains, undergoes aCa2+-dependent conformational change that allows it tohomodimerize at the membrane. Through extracellularinteractions with E-cadherins on a neighbouring cell,opposing cadherin dimers can integrate the actincytoskeletons. Stabilization of intercellular adhesion requiresthe cytoplasmic domain of E-cadherin, which binds to β-catenin. β-catenin, in turn, binds α-catenin, which iscentral in recruiting a number of cytoskeletal proteins,including the filamentous (F)-actin-nucleating forminproteins (Fmn), and the actin-binding proteins vinculin,Ajuba, myosin VIIa, vezatin, α-actinin and members of thevasodilator-stimulated phosphoprotein (VASP) family of F-actin-elongating proteins. At least some of theseinteractions are essential in polymerizing and organizingactin into cables that help to seal membranes and integratethe actin cytoskeleton across the epithelial sheet. Bycontrast, p120 catenin (p120), which is related to β-catenin,binds to E-cadherin through a juxtamembrane domain andseems to function in cadherin turnover, perhaps byregulating cadherin trafficking. An emerging intercellularadhesion system (not shown), consisting of nectin andafadin, also has roles in the organization of a range ofintercellular junctions. Nectin is a Ca2+-independent,immunoglobulin-like, intercellular adhesion molecule, andafadin is a nectin- and actin-filament-binding protein thatconnects nectin to the actin cytoskeleton78,79.

Ca2+

Ca2+

Ca2+

Ca2+

Ca2+

Ca2+

Ca2+

Ca2+

α-catenin α-catenin

α-actinin

VASP

?

VezatinAjuba

F-actin

p120 p120

β-catenin β-catenin

Vinculin Vinculin

Vinculin

Fmn Fmn

Myosin VIIa

Plasma membrane EC domain

Table 1 | Amino-acid sequence identities (and similarities) between mouse α-catenins/vinculin*

αE-catenin αN-catenin αT-catenin α-catulin Vinculin

αE-catenin 100% 76.5% (83.1%) 56.1% (73.7%) 24.8% (33.9%) 22.5% (31.0%)

αN-catenin – 100% 58.5% (69.6%) 25.6% (32.8%) 22.3% (30.0%)

αT-catenin – – 100% 19.7% (32.1%) 17.3% (30.3%)

α-catulin – – – 100% 18.6% (23.7%)

Vinculin – – – – 100%

*Data are from REF. 7.



cDNA encoding a protein that was 80% identical to αE-catenin (CAP102) but that contained a 48-residueinsert26. The CTNNA2 gene maps to human chromo-some 2p12–p11.1, which is homologous to the B3-Dregion of mouse chromosome 6 (34.2).

αN-catenin localizes to adherens junctions that bor-der ACTIVE ZONES in developing and mature synapsesthroughout the developing and postnatal brain43,44. Theexpression of specific cadherin subtypes delineatesspecific neuronal circuits, which indicates thatcadherin–catenin complexes mediate adhesion betweenpre- and postsynaptic membranes45–47. Interestingly, theclassic mouse mutation cerebellar deficient folia (cdf)results from a deletion in the αN-catenin gene, and cdfmice show ataxia, cerebellar hypoplasia and abnormalcerebellar lobulation48.Approximately 40% of the PURKINJE

CELLS in these animals are located ectopically in the whitematter and inner granule-cell layer (FIG. 3). Transgenicre-expression of the αN-catenin transgene in these micerestored normal cerebellar morphology. Taken together,these findings underline a role for αN-catenin in stabiliz-ing N-cadherin-mediated synapse formation during thedevelopment of the central nervous system48.

αT-catenin. αT-catenin (encoded by CTNNA3) is pre-dominantly expressed in the heart and testis27. Thehuman and mouse CTNNA3 genes contain 18 exons,the boundaries of which are identical to those in thehuman CTNNA2 gene49. αT-catenin seems to be func-tionally equivalent to αE-catenin on the basis of its abil-ity to restore cell–cell adhesion in a colon-cancer cellline in which the CTNNA1 gene is mutated27. Because ofits chromosomal position (10q21) and its high level ofexpression in the heart, CTNNA3 has been deemed tobe a candidate for a form of DILATED CARDIOMYOPATHY thathas been linked to human chromosome 10q21–q23(CMD1C). However, mutation screening of all 18 exonsof the CTNNA3 gene in one family that is affected bythis disease failed to uncover any mutations49.

α-catulin. Catenin α-like-1 — or α-catulin (encoded byCTNNAL1) — was first characterized as a 2.45-kb tran-script that was downregulated in human pancreaticcancer cells28. In vitro transcription and translation of

regeneration. In this model, although αE-catenin wouldnot be mutated, it might be transiently inactivated, per-haps through post-translational modification or associa-tions with other proteins.

αN-catenin. αN-catenin (encoded by CTNNA2) orcadherin-associated-protein related (CAPR) was firstcharacterized by Claverie and colleagues as a human

ACTIVE ZONES

The sites along nerve terminalswhere synaptic vesicles dock andundergo Ca2+-dependentexocytosis during synaptictransmission.

PURKINJE CELLS

Large neurons with extensivedendritic projections that form alayer near to the surface of thecerebellum.

DILATED CARDIOMYOPATHY

Also known as ‘congestivecardiomyopathy’, this is the mostcommon form of myocardialdisease, which causes decreasedsystolic function and increasedventricular volume.

Table 2 | Members of the α-catenin/vinculin family and their functions

Family member Chromosome localization Cellular Phenotype(human/mouse) localization

αE-catenin 5q31/18q11.0 Adherens junctions Lethal at the blastocyst stage

αN-catenin 2p12–p11.1/6-B3D Adherens junctions Cerebellar deficient folia

αT-catenin 10q21–q23 Adherens junctions ND

α-catulin 9q22–q32/4-C1 ND ND

Vinculin 10q21–q23/14-A2 Focal contacts and Lethal by embryonic day 10adherens junctions

The α-catenin/vinculin-family members are crucial for the formation of proper adherens junctions during development, as judged by thephenotypes of the knockout animals. αE-catenin is required at the blastocyst stage and without this protein, the outer epithelial covering(trophectoderm) of the developing embryo lacks integrity. Loss of αN-catenin results in the cerebellar deficient folia (cdf) phenotype withataxia, cerebellar hypoplasia and abnormal cerebellar lobulation. Vinculin knockout results in heart and brain defects during embryonicdevelopment. Vinculin-mutant embryos are also 30–40% smaller, growth of their somites and limbs are retarded, and their ectodermaltissues are sparse and fragile112. ND, not determined.

Figure 3 | Abnormal cerebellar development in αN-catenin-mutant mice. Mutations inthe αN-catenin gene underlie the genetic defect in the ataxic cerebellar deficient folia (cdf)-mutant mice. The cerebella of cdf/cdf-mutant mice show hypoplasia and abnormallobulation. a | A schematic representation of the midline sagittal sections from wild-type andcdf/cdf-mutant mouse brain cerebella shows scattered Purkinje cells in the more centralwhite matter and abnormal lobulation (blue stars). The magnified region (b) shows thestructure of the cerebellar cortex (the grey matter), which includes the cell bodies anddendrites of the Purkinje cells; the axons of the granule cells; and the cell bodies, dendritesand axons of the basket cells.

Wild typea

b

cdf/cdf

Basket cell

Purkinje cell

Purkinje axon

Climbingfibre

Granulecell

Mossyfibre

Cerebellar cortex

White matter

Granular layer

Purkinje-cell layer

Molecular layerParallel fibre

Stellate cell

Golgicell


R E V I E W S

proteins. Actin and α-actinin are well-characterizedbinding partners of both proteins52–56, and there is sub-stantial evidence of a direct interaction between vin-culin and β-catenin in vivo57.

The actin-binding domains in both vinculin(which contains a bipartite actin-binding site) andαE-catenin are localized in their carboxy-terminal seg-ments (residues 893–985/1016–1066 and 697–906,respectively; FIG. 4)58–60. Vinculin is interesting in that itshead and tail segments can interact with each other toprovide a conformational state that precludes its abilityto associate with focal-complex proteins and with theactin cytoskeleton61,62. On signal-transduction-medi-ated activation of focal-complex assembly, however,activated phospholipids can change the conformationof vinculin associated with its partners talin (an actin-binding protein that binds directly to integrins) andactin (reviewed in REFS 63,64). A priori, it might betempting to speculate that the similarity of αE-cateninto vinculin means that it too can undergo autoregula-tion. However, the head-to-tail interactions of vinculinhave been strongly detected by yeast two-hybrid analy-ses, whereas corresponding αE-catenin interactionshave not been found (REF. 50 and A.K. et al., unpub-lished data). One possibility is that the lack of a pro-line-rich hinge region in αE-catenin, which is presentin vinculin, yields a less flexible structure, which mightprevent the head-to-tail interaction65.

Despite sequence and structural differences thatresult in different modes of regulation and only par-tially overlapping binding partners, both vinculin andαE-catenin participate in coordinating actin dynamicsat their respective adhesive junctions.Vinculin seems tobe more important at integrin-mediated junctions,whereas αE-catenin seems to be exclusive for adherensjunctions. Despite these differences, the association ofαE-catenin with E-cadherin–β-catenin complexes andactin must be intricately regulated in a manner thatseems conceptually, if not mechanistically, analogous tothe coordinated association of vinculin with talin andactin. Whether αE-catenin changes its ligand-bindingability through post-translational modification,localized activation of phospholipids or dynamicinteractions with other proteins remains an impor-tant question for the future.

Three-dimensional structure of the M-fragment ofαE-catenin. To define the segments of αE-cateninthat are necessary for mediating intercellular adhe-sion, sequences that encode the extracellular andtransmembrane domains of E-cadherin were fused tovarious segments of αE-catenin cDNA, and the trans-genes were tested for the ability of their encodedfusion proteins to induce the rapid aggregation ofmouse L CELLS66. This led to the identification of theintercellular adhesion modulation (M) domain(residues 509–643, which partially includes the VH2domain) of αE-catenin. In this assay, weak intercellu-lar adhesion was facilitated by an E-cadherin–M-domain fusion protein, whereas a fusion proteincontaining E-cadherin and the full-length αE-catenin

the cloned transcript yielded an 82-kDa protein thatshares 24.8% identity with αE-catenin. The humanCTNNAL1 gene maps to chromosome 9q22–q32(mouse chromosome 4 band C1)28. α-catulin mRNA isexpressed ubiquitously, although the levels are lower inneural tissues. At 734 amino acids, the predicted α-cat-ulin polypeptide is smaller than αN- and αE-catenin; itlacks the central 110-residue region and has a shortercarboxyl terminus. It is not yet known whether α-cat-ulin localizes to cell–cell borders or is a component ofadherens junctions. However, the amino-terminalAMPHIPATHIC HELICES of α-catenin that are thought toensure an interaction with β-catenin are also present inα-catulin. Furthermore, amphipathic helices in thecarboxy-terminal part of vinculin and α-catenin,which allow these proteins to bind to the actincytoskeleton, are also present in α-catulin29. So,sequence homology between α-catulin and α-cateninor vinculin implies that α-catulin might have the poten-tial to bind to β-catenin and the actin cytoskeleton.

YEAST TWO-HYBRID ANALYSES have uncovered the lym-phoid blast crisis oncogene (LBC) Rho GUANINE

NUCLEOTIDE-EXCHANGE FACTOR (LBC Rho-GEF) as a partnerfor α-catulin but not for αE-catenin, which indicatesthat α-catulin might have a new role in modulating sig-nalling by the Rho pathway29. It will be interesting to seehow the functions and associations of α-catulin differfrom those of the ‘classic’α-catenins.

αE-catenin structureSequence similarities and structural relationships.Because of three extended regions of sequence similaritythat are shared by αE-catenin and its distant cousin vin-culin (known as the vinculin-homology (VH) domainsVH1–VH3), αE-catenin has been described as a relativeof vinculin24,34,50,51 (FIGS 4,5). Although the degree of iden-tity is not high, these homologies are regarded as biolog-ically meaningful, not only because both moleculesanchor actin filaments to the plasma membrane, butalso because some ligand-binding sites map to theregions that are more highly conserved between the

AMPHIPATHIC HELICES

Helical structures that consist ofhydrophobic non-polar residueson one side of the helicalcylinder, and hydrophilic andpolar residues on the other side.

YEAST TWO-HYBRID ANALYSIS

A technique that is used to studyprotein–protein interactions in vivo in yeast cells.

GUANINE NUCLEOTIDE-

EXCHANGE FACTOR

A protein that facilitates theexchange of guaninediphosphate (GDP) for guaninetriphosphate (GTP) in thenucleotide-binding pocket of aGTP-binding protein.

L CELLS

Cells of a mouse fibroblast linethat is derived from connectivetissue and does not expressclassic cadherin molecules.

Figure 4 | Sequence similarities between vinculin and αE-catenin. The coloured areasrepresent regions of similarity between the two proteins. The degrees of amino-acid identity areindicated as percentages. The magenta region in vinculin represents the proline-rich hingesegment. Actin-binding domains are marked as the red open boxes (amino acids 697–906 forαE-catenin and 893–985/1016–1066 for vinculin). The intercellular adhesion modulation (M)domain (residues 509–643) of αE-catenin is marked as the blue open box. The numberscorrespond to amino acids of the protein sequence. VH, vinculin-homology domain.

22

6 208 582 796 905 1,053 1,066

377 586 697 848 906224

27% 31% 34%

VH1 VH2 VH3

αE-catenin

Vinculin



Crystallographic analysis of the so-called M-fragment(residues 377–633), which includes the M-domain,detected a tandem repeat of a four-α-helix bundle. Thisis structurally related to the vinculin tail67 (FIG. 5).Overall, these findings indicate that αE-catenin proba-bly comprises a series of repeating antiparallel α-heli-cal domains.

In solution, the M-fragment can form relatively low-affinity dimers67. On the basis of the findings ofImamura and colleagues66, it seems likely that, throughweak dimerization of the M-domain of αE-catenin,the lateral dimerization of E-cadherin molecules inthe plasma membrane might be enhanced and/or stabi-lized, thereby promoting and/or strengthening cell–celladhesion68,69.

Dimerization and β-catenin-binding domains of αE-catenin. In vitro binding assays indicate that classiccadherins, β-catenin and αE-catenin assemble into acomplex with a 1:1:1 stoichiometry70.αE-catenin forms ahomodimer in solution at micromolar concentrations56,62;however, in the presence of β-catenin or plakoglobin,the homodimer dissociates and a 1:1 heterodimer ofαE-catenin and β-catenin/plakoglobin is observed62,71.Indeed, the two processes seem to be mutually exclu-sive, as judged by the fact that the site on αE-catenin forβ-catenin binding (residues 54–148)62,71–74 overlaps withthat for homodimerization (residues 82–279)62,71. Thecrystal structure of this domain indicates that αE-catenindimerizes through the formation of a four-helix bundlein which two antiparallel helices are contributed by eachprotomer. The precise role of homodimerization inadherens-junction assembly remains unclear. Oneattractive possibility is that the transition betweenhomo- and heterodimer occurs at the cell membrane,which enables a β-catenin-induced conformationalchange to influence the association of αE-catenin withother partners — for example, actin filaments and/ortheir polymerizing machinery. It is not clear how thisrelates to the potential dimerization of αE-cateninthrough the M-domain or the possible enhancement ofE-cadherin lateral dimerization.

αE-catenin and the actin cytoskeletonProteins that link αE-catenin to actin. Studies of KER-

ATINOCYTES in which the αE-catenin gene (CTNNAI) hasbeen conditionally inactivated have uncovered a role forαE-catenin in the formation of the radial actin cablesthat are necessary for stabilizing adherens junctions,sealing membranes and assembling epithelial sheets18,39.During the initial steps of epithelial-sheet formation,linear radial actin cables assemble at nascent intercellu-lar adherens junctions; this process requires αE-cateninand actin polymerization.

αE-catenin was postulated to interact directly withfilamentous (F)-actin75, and a direct interaction wasconfirmed by Rimm and co-workers56. Biochemicaland genetic approaches have uncovered domains inαE-catenin that mediate further interactions withactin-binding proteins (FIG. 6), which have provided newinsights into the importance of αE-catenin in actin

conferred considerably stronger adhesion. Althoughother explanations are possible, the underlying differ-ence is likely to reside, at least in part, in the need fornot only the M-domain but also the domain that isinvolved in actin-based cytoskeletal interactions,which are known to be required for stable intercellu-lar adhesion37,66.

KERATINOCYTES

Differentiated epithelial cells ofthe skin.

Domain 1

Domain 2

B

A1

A2

D

C

E

F G

H

COOH

NH2

H0 H5 H4

H3H2

H1

A1

DH E

H5

H0

a

c

b

Figure 5 | Comparison of the crystal structures of the αE-catenin M-fragment and vinculintail. The crucial functions of αE-catenin and vinculin are to mediate protein–protein andprotein–phospholipid interactions. Proteins composed of tandemly repeated α-helical bundlesprovide a structural framework for the assembly of multiprotein complexes. a | View of the αE-catenin M-fragment structure with two four-helix domains (domains 1 and 2) coloured from theamino terminus (blue) to the carboxyl terminus (red). Letter labels for each of the helices are shown.b | The crystal structure of the carboxy-terminal part of vinculin comprises five helices (H0–H4). c | A comparison of the αE-catenin M-fragment domain 1 (red/orange; left) and domain 2 (green;middle) with the vinculin-tail domain (dark/light blue; right). Parts a and c courtesy of D. Barford andreproduced with permission from REF. 67 © (2001) Macmillan Magazines Ltd; part b courtesy of D.R. Critchley, Biochemistry Department, University of Leicester, UK and reproduced with permissionfrom REF. 113 © (1999) Elsevier.


R E V I E W S

Although the presence of Ena/VASP proteins issufficient to explain the addition of actin subunits topreexisting actin filaments, it might not be sufficientto account for de novo actin polymerization. Recently,however, we identified isoforms of formin-1(FMN1), the founding member of the FORMIN FAMILY,as binding partners for αE-catenin and as candidatesfor generating the radial actin cables that assemble atnascent adherens junctions80. Using yeast two-hybrid and in vitro analyses, a region in the amino-terminal segment of several isoforms of FMN1 wasshown to interact specifically with residues~300–500 of αE-catenin. The conserved forminhomology (FH) domains in the carboxy-terminalportion of FMN1 contain sites for the nucleation ofactin polymerization (reviewed in REF. 81). The carboxy-terminal segment of FMN1 can nucleate the polymer-ization of unbranched actin filaments in vitro andfunction in transfected cells in an αE-catenin-depen-dent fashion to promote the polymerization of radialactin filaments80. When transiently expressed, the car-boxy-terminal portion of another formin, diaphanousprotein homologue-1 (Dia1) also localizes to adherensjunctions (reviewed in REF. 81). Because the FMN1domain that associates with αE-catenin does notseem to be conserved in Dia1, it remains unclearhow this carboxy-terminal segment of Dia1 isrecruited to junctions. However, recent in vitro stud-ies indicate that Dia1 might also nucleate actin poly-merization82, and then associate with, and moveprocessively along, the growing end of actin fila-ments in cells83.

Although FMN1 and Dia1 have surfaced as goodcandidates to initiate the formation of linear actin cablesat sites of nascent adherens junctions, it remains to bedetermined whether these, or any other formins in theirnative state, are functional at these sites, and, if so, howthey are regulated to control actin polymerization.Given the complexity and possible redundancy withinthe mammalian formin family, resolving formin func-tions might be best addressed in lower eukaryoticsystems. Irrespective of mechanism, once they areassembled at nascent junctions, actin filaments seem tobundle into linear cables. α-actinin is a candidate forthis bundling, as it is known to form antiparallel dumb-bell-like structures and thereby place an F-actin-bindingsite at each pole of an α-actinin dimer. Radial actincables at junctions seem to function with myosins andgenerate tension across a growing epithelial sheet84. Insearching for a binding partner for myosin VIIA, Kussel-Andermann and colleagues85 have identified anotherprotein that links adherens junctions and the acto-myosin-based contractile system37. Known as vezatin,this protein interacts with myosin VIIA and the car-boxy-terminal region of αE-catenin. This interactionhas prompted speculation that myosin VIIA, whenanchored by vezatin to the adherens junctions, mightuse the actin cytoskeleton to generate tension, therebystrengthening cell–cell adhesion.

Finally, αE-catenin interacts directly with spectrin,which is an important component of the skeleton that

dynamics (reviewed in REFS 50,76). α-actinin and vinculinwere among the first binding partners of αE-catenin tobe described60,66,73,77; both interact with similar residuesin αE-catenin and can bind actin directly. The carboxy-terminal 280 residues of αE-catenin interact with thezonula occludens-1 (ZO1) protein, which is also able tobind actin directly66.

Another binding partner of αE-catenin is afadin,which is known to bind to F-actin and might recruit itto sites of nascent adherens junctions. Afadin also asso-ciates with the protein nectin, which forms the trans-membrane core of another intercellular adhesionsystem78,79. Other associates of αE-catenin includevasodilator-stimulated phosphoprotein (VASP) andEnabled (Ena), which localize to adherens junctions inan αE-catenin-dependent fashion39. Whether theseinteractions are direct or indirect is not yet clear, asαE-catenin also associates directly with members of thezyxin family, which can also bind actin and/or recruitmembers of the Ena/VASP families52. Irrespective of howVASP gets to the adherens junctions, both Ena andVASP can bind to the actin-monomer-binding proteinprofilin, which promotes the addition of ATP–actinmonomers to actin filaments. VASP has recently beenshown to compete with capping protein for the BARBED END

of pre-existing actin filaments, which provides a mecha-nism for how VASP promotes the extension of actinpolymers (reviewed in REF. 4).

BARBED END

The fast-polymerizing end of anactin filament, which is definedby the arrowhead-shapeddecoration of actin filamentswith myosin fragments.

FORMIN FAMILY

A family of multidomainscaffold proteins that areinvolved in actin-dependentmorphogenetic events. They areconserved from fungi to humansand are characterized by thepresence of two conservedcarboxy-terminal regions: theformin homology (FH) domainsFH1 and FH2.

Figure 6 | Functionally important regions of αE-catenin. This schematic of αE-cateninillustrates its three vinculin homology (VH) domains (VH1–VH3). The direct binding partners for αE-catenin are listed on the right, and the corresponding domain diagrams denote the regionsand encompassing amino-acid residues of αE-catenin that have been identified as biochemicallyessential for the interaction. αE-catenin interacts with E-cadherin–β-catenin complexes throughits amino-terminal β-catenin-binding domain. In solution, αE-catenin forms a homodimer throughits dimerization domain. When αE-catenin associates with E-cadherin–β-catenin complexes,however, the αE-catenin homodimer dissociates, and heterodimers of α- and β-catenin areformed. The intercellular adhesion modulation (M) domain, which partially includes the VH2domain of αE-catenin, defines the segments of αE-catenin that are necessary for mediatingintercellular adhesion. The carboxy-terminal region, which includes the VH3 domain of αE-catenin, overlaps with the filamentous (F)-actin-binding domain. The vinculin-, α-actinin- andformin-1-binding domains on αE-catenin facilitate organization of the F-actin cytoskeleton andthe regulation of actin dynamics during the formation of stable intercellular adhesions.

αE-catenin

Binding

Dimerization domain

F-actin

Adhesion modulation domain

Vinculin

Formin-1

β-catenin/plakoglobin

α-actinin

1 22

54 148

82 279

697 906

509 643

327

325

300 500

394

697 906402

224 377 586 697 848 906

VH1 VH2 VH3



Once nascent adherens junctions (known aspuncta) have assembled from clusters of transmem-brane E-cadherin molecules and their cytoplasmicassociates (β-catenin and αE-catenin), the contacts arestabilized by a second step that involves the attachmentand/or de novo assembly of a linear radial actin cable atthe tip of each punctum38,39,90. Proteins of the VASP andmammalian orthologue of Ena (MENA) families local-ize to these sites, and studies using a dominant-negativeform of VASP imply that VASP might have a role inmediating intercellular adhesion in both cultured cellsand transgenic mice39. As outlined above, functionalstudies support a role for these proteins in the elonga-tion of pre-existing actin filaments89, and there arenumerous ways in which developing adherens-junctioncomplexes can bind to actin and potentially help torecruit F-actin.

The findings that imply a role for formins atadherens junctions are also intriguing, particularly giventhe broad role of formin-family members in stimulatingde novo polymerization of linear radial actin cables (forreviews, see REFS 81,91). As outlined above, if nativeformins localize to cell–cell junctions and participate inregulating the formation of linear actin cables, then aninteresting issue to address will be whether differentformin-family members have redundant or distinctroles in intercellular adhesion. Equally important will bewhether Ena/VASP and formin-family members worktogether to assemble radial actin cables, or whetherthese proteins function independently, perhaps inresponse to different cellular cues.

αE-catenin binding to E-cadherin–β-cateninMany events in organized epithelia, such as cytokine-sis and cell migration, require dynamic remodelling ofadhesive contacts. Once again, αE-catenin seems to beintricately involved in these processes. Whereas newlysynthesized E-cadherin associates with β-catenin inthe endoplasmic reticulum, αE-catenin seems to jointhe E-cadherin–β-catenin complex only after it hasreached the plasma membrane92. Conversely, detach-ment of αE-catenin and actin from the E-cadherin–β-catenin complex has been observed during the disas-sembly of adherens junctions93.

Although it is not yet clear precisely how the associa-tion of αE-catenin with E-cadherin–β-catenin com-plexes is regulated, the Armadillo subfamily of catenins(β-catenin, plakoglobin and p120 catenin) seems to beinvolved. On signalling from tyrosine-kinase growth-fac-tor receptors, or in response to overexpression of non-receptor tyrosine kinases,β-catenin is phosphorylated —an event that is accompanied by a decrease in adhesion4,94

and a loss of cytoskeletal anchorage to cell–celljunctions95. Moreover, in cells that are treated with per-vanadate, which is an inhibitor of phosphotyrosine phos-phatases, tyrosine phosphorylation of β-catenin andplakoglobin correlates with the dissociation of αE-cateninfrom the E-cadherin–β-catenin complex96.

Rho-family GTPases also participate in regulatingcadherin-mediated cell adhesion (reviewed in REF. 97).Although several mechanisms are possible and, in fact,

underlies and reinforces the plasma membrane. Thebinding of spectrin to adherens-junction complexesmight stabilize intercellular adhesion by integratingthe complexes into this macromolecular membranestructure86.

Why so many connections? Given the nature of themany associates of αE-catenin, it seems likely that thisprotein is a central player in nucleating the assembly of amultiprotein complex that links E-cadherin–β-catenincomplexes to F-actin. Certainly, the CTNNA1-null ker-atinocytes described above illustrate the importance ofthis process not only for stabilizing intercellular junc-tions, but also for coordinating actin dynamics at thesesites18,39 (FIG. 7). But why are there so many different waysto connect αE-catenin with actin dynamics?

One factor that might help to explain the diversity inpotential binding surfaces for actin at adherens junc-tions is the range of cytoskeletal changes that mustoccur in epithelial cells for them to establish stablecell–cell contacts and assemble into epithelial sheets.Some insights into these dynamics stem from video-microscopy studies of cells that express actin or cad-herin bound to green fluorescent protein (GFP) whileCa2+ levels are raised and epithelial sheets form37,84,87.

During the initial steps of establishing cell–cell con-tacts, activated Cdc42 and Rac, which are members ofthe Rho family of small GTPases, stimulate the exten-sion of FILOPODIA and LAMELLIPODIA, respectively5,37,39,84,88.The Arp2/3 PROTEIN COMPLEX has been implicated in nucleat-ing actin polymerization and producing the extensivebranched cortical meshwork of F-actin that developsbeneath the membrane at Rac-stimulated lamellipodia(reviewed in REF. 89). Lamellipodial extensions generatelarge dynamic contacts between the surfaces of appos-ing cells. By contrast, filopodia-like extensions involvethe polymerization of linear actin filaments and seem tobe much more rapidly formed. Filopodia have beenimplicated in the generation of homophilic interactionsbetween two opposing E-cadherin–β-catenin com-plexes at the tips of the cell–cell contact sites.

FILOPODIA

Thin, transient actin protrusionsthat extend out from the cellsurface and are formed by theelongation of bundled actinfilaments in its core.

LAMELLIPODIA

Cellular protrusions that containextensively branched arrays ofactin filaments, which areorientated with their plus(barbed) ends toward theplasma membrane.

Arp2/3 PROTEIN COMPLEX

A complex that consists of twoactin-related proteins, Arp2 andArp3, along with five smallerproteins. When activated,the Arp2/3 complex binds to theside of an existing actin filamentand nucleates the assembly of anew actin filament. The resultingbranch structure is Y-shaped.

Figure 7 | Model of adherens-junction formation in keratinocytes. a | Initial cell–cell contactsare formed by opposing E-cadherin–β-catenin complexes at the tips of filopodia or lamellipodia.These initial contacts are nascent adherens junctions and are termed puncta. b | In the presenceof αE-catenin, formin and other proteins such as VASP (vasodilator-stimulated phosphoprotein)that bind to αE-catenin and/or the actin cytoskeleton, bundles of radial actin cables assemble oneach side of the puncta and form anchors to the underlying cortical actin ring. c | As aconsequence of actin reorganization, mature adherens junctions are formed.

a b c

E-cadherin–β-catenin αE-catenin, formin, VASP Actin monomers Actin filament


R E V I E W S

The ability of E-cadherin to compete with tran-scription factors for β-catenin raises the question ofwhether the loss of αE-catenin might also affect thestatus of WNT signalling — perhaps by negativelyaffecting the stability of E-cadherin–β-catenin com-plexes and increasing the soluble pool of β-catenin.Although this is theoretically possible, the gene-tar-geting studies that have been carried out so far do notsupport this idea; for example, when mice in whichαE-catenin was conditionally deleted in the develop-ing skin were mated with WNT-reporter-expressingmice, no increase in the activity of β-catenin–tran-scription-factor complexes was detected, despite theincrease in epidermal-cell proliferation18. So, althoughαE-catenin expression clearly restores the normalphenotype to αE-catenin-mutant cancer cells, themechanisms by which αE-catenin loss influencestumorigenesis might be distinct from those caused byeither E-cadherin loss or β-catenin overactivation. Thesustained activation of the Ras–ERK/MAPK pathwayin skin epidermis that lacks αE-catenin expression pro-vides one possible mechanism, which goes beyond asimple loss of cell–cell adhesion.

Potential nuclear partners for αE-cateninThe discovery that β-catenin can associate with andactivate transcription factors in response to WNT sig-nalling has been followed by more than a decade ofresearch linking intercellular adhesion to transcrip-tional regulation and cancer7–9. Other interactionsbetween cell-junction proteins and nuclear factorshave since been detected106, and αE-catenin seems tobe no exception.

Ajuba, which is a member of the zyxin family ofproteins, has been shown to interact directly withαE-catenin107. Interestingly, whereas zyxin localizes tofocal adhesions, which can be considered to be cell–sub-stratum junctions, Ajuba localizes to cell–cell junctions.Through its dual association with the amino-terminalsegment of αE-catenin and with F-actin, Ajuba mightcontribute to the coupling of adherens junctions to theactin cytoskeleton. Like zyxin, however, Ajuba has alsobeen detected in the nucleus, and so has the intriguingpotential to coordinate the regulation of transcriptionand cell adhesion108. Although further studies will benecessary to assess whether this hypothesis is correct,Ajuba joins β-catenin as a protein that localizes to boththe nucleus and adherens junctions.

Another potentially interesting αE-catenin associatethat is worth mentioning in this context is FMN1. Fmn1was first identified as the gene that was mutated inmouse embryos that were homozygous for the limbdeformity (ld) mutation109. FMN1 is the foundingmember of the formin family, and it has only morerecently become apparent that a mutation in a formingene leads to a disruption in the establishment of theSonic hedgehog (SHH)–FGF4–BMP (where FGF standsfor fibroblast growth factor and BMP is bone morpho-genetic protein) feedback loop that is necessary for theformation of the apical ectodermal ridge (the layer ofsurface ectodermal cells at the apex of the embryonic

are likely to account for this, it is known that IQGAP1,which is a target of activated Cdc42 and Rac1GTPases, binds to β-catenin and induces the dissocia-tion of αE-catenin from the E-cadherin–β-catenincomplex98. On the basis of these data, the associationof αE-catenin with the E-cadherin–β-catenin com-plex seems a probable target for the functional modu-lation of this complex.

αE-catenin and tumour formationSeveral studies imply that the disruption of cadherin-based adhesion is a main step in the progression ofhuman epithelial cancers. Reduced levels of E-cadherinand αE-catenin proteins seem to be characteristic ofmany different human cancers, including malignanttumours of the breast, colon, stomach, oesophagus,bladder and liver13,15–17,99–101. The proportion of suchtumours that fail to express one or both of these pro-teins has been reported to be as high as 80%, and theloss of E-cadherin or αE-catenin often correlates withthe degree of tumour differentiation and metasta-sis13,102–104. The loss of αE-catenin seems to be the morecommon event, and also correlates better than the lossof E-cadherin with the level of invasiveness of a tumourand with its degree of differentiation13,102. αE-catenin isabsent or markedly depleted in several human cancercell lines, including the lung cancer cell line PC9 (REF. 10)

and the prostate adenocarcinoma cell line PC3 (REFS 11,12).If αE-catenin is artificially reintroduced into PC3cells, E-cadherin-dependent adhesion is restored andthe invasive phenotype is suppressed11. In this respect,αE-catenin seems to function as a tumour suppressor,similar to several of the classic cadherins.

The seminal work of Shimoyama and co-workersassociated a loss of αE-catenin-gene function withhuman cancer by showing downregulation of theexpression of αE-catenin in PC9 cells followinghomozygous deletion of part of the αE-catenin gene10.Bullions and colleagues, however, have taken the connec-tion one step further by identifying a mutation in theαE-catenin gene in cells that are derived from an ovariancarcinoma14. The Ov2008 αE-catenin mutation results inan amino-terminally truncated form of the protein thatlocalizes to the cytoplasm and does not bind β-cateninefficiently. Again, restoration of wild-type αE-cateninexpression restricted the uncontrolled growth of the cellsand restored a normal adhesive morphology.

As mentioned above, mutations in E-cadherin havealso been found in human cancers and E-cadherin hasbeen shown to have growth-suppressor activity. Onthe basis of cell-culture studies, some of the tumour-suppressor effects of E-cadherin might be adhesionindependent. As E-cadherin binds to β-catenin, cellsthat have appreciable soluble pools of β-cateninmight respond to elevated E-cadherin levels by sup-pressing the transcription of LEF1/TCF-regulatedgenes105. Conversely, a loss of E-cadherin expressionmight, in certain instances, resemble sustained acti-vation of Wingless/WNT-related (WNT) signalling,which has a well-established link to some types ofhuman cancer.



Studies of many of these connections are still intheir infancy. In the future, it will be important toestablish what conformational changes or proteinmodifications are involved in the selective recruit-ment of αE-catenin to E-cadherin–β-catenin com-plexes at the plasma membrane. What are the mainmolecular steps that are involved in regulating howαE-catenin selectively associates with and activatesthe actin-polymerizing/organizing machinery? Doformins have overlapping functions, particularly inepithelial-sheet formation? It is also possible thatindividual formins or formin isoforms might havedistinct functions.

In addition, the precise roles of the Rho-familyGTPases and the Ena/VASP-family members in regu-lating cadherin-mediated junction formation remainto be discovered. It is not known how broadly usedthese mechanisms are, or how they are involved in thefunctions of specific α-catenin-family members. DoesαE-catenin strictly regulate actin-cytoskeletal dynam-ics at adherens junctions, or does it also have a role inpolarizing the microtubule cytoskeleton? It is not clearwhether Ajuba or other αE-catenin-associated pro-teins function as integrators of cell adhesion and tran-scriptional regulation, and, if so, under what circum-stances this might occur. Finally, what mechanisms areinvolved in cadherin and αE-catenin dysregulation,which occurs during tumorigenesis and metastasis?

Finding the answers to these questions will keepinvestigators in the α-catenin and associated actin-dynamics fields occupied for the coming decade.However, as these answers unfold, we will be in a con-siderably better position to determine the extent towhich α-catenin fits the role of the gatekeeper at thecrossroads of adherens junctions, cytoskeletal dynamicsand gene expression.

limb bud). Interestingly, expression of Gremlin, whichis a BMP-inhibitory protein, is lost in the ld-mutantmouse and grafting Gremlin-expressing cells into ld-mutant limb buds restores the feedback loop110. Recentstudies imply that mutations in the Grem1 gene are suf-ficient to cause the ld phenotype without apparent con-sequence to Fmn1 expression111. As the Grem1 mutationfails to complement the ld mutation, it has been sug-gested that the ld phenotype might reflect defects inGrem1-gene transcription, rather than unveiling a rolefor FMN1 per se111. Although this reveals a functionalrole for Gremlin, it leaves open the functional impor-tance of FMN1. Further studies, removing redundanciesamong formin-family members, will probably berequired to address this intriguing issue.

Conclusions and perspectivesAlthough it has not been as extensively studied as itsprominent partner β-catenin, αE-catenin has come intoits own in recent years as an essential component ofadherens junctions that can also integrate adhesion withother essential cellular events. It is well established thatαE-catenin is a central protein not only in linking theactin cytoskeleton to E-cadherin–β-catenin complexes,but also in recruiting a range of other important pro-teins to developing intercellular junctions. Some ofthese proteins, such as members of the Ena/VASP andformin families, seem to be important in regulatingactin polymerization at developing junctions. Others,such as vezatin and α-actinin, probably participate ingenerating force or tension at the interface betweenactin and adherens junctions. Others still, such as spec-trin, might integrate the adherens junctions with theunderlying cortical network, whereas Ajuba might gen-erate crosstalk between junctions and the transcrip-tional state of the cell.

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AcknowledgementsWe are grateful to D. Barford and D. R. Critchley for providing uswith images. E.F. is an investigator at the Howard Hughes MedicalInstitute, New York, USA. A.K. is a research associate supported bythe US National Institutes of Health.

Competing interests statementThe authors declare no competing financial interests.

Online links

DATABASESThe following terms in this article are linked online to:Entrez Gene:http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geneCTNNA1 | CTNNA2 | CTNNA3 | CTNNAL1 | Fmn1 | Grem1Swiss-Prot: http://www.expasy.chAjuba | Armadillo | β-catenin | α-catulin | desmoplakin | DIA1 | E-cadherin | αE-catenin | FGF4 | FMN1 | gremlin | HMP1 | HMP-2 |HMR-1 | IQGAP1 | LEF1 | myosin VIIA | αN-catenin | p120 catenin |plakoglobin | SHH | VASP | vezatin | vinculin | ZO1Access to this interactive links box is free online.

α-catenin: at the junction of intercellular adhesion and actin dynamics

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