RolesofCadherinsandCateninsin Cell Adhesion and Epithelial ...download.xuebalib.com/5id6COUoQLjc.pdf · Introduction: The Basic Design of Polarized Epithelial Cells 4 2. Cadherin-Mediated

CHAPTER ONE

Roles of Cadherins and Catenins inCell�Cell Adhesion and EpithelialCell PolarityW. James Nelson*,†,‡, Daniel J. Dickinson‡,1, William I. Weis†,‡,}*Department of Biology, Stanford University, Stanford, California, USA†Department of Molecular and Cellular Physiology, Stanford University, Stanford, California, USA‡Cancer Biology Program, Stanford University, Stanford, California, USA}Department of Structural Biology, Stanford University, Stanford, California, USA1Present address: Department of Biology, University of North Carolina, Chapel Hill, North Carolina, USA

Contents

1.

ProgISShttp

Introduction: The Basic Design of Polarized Epithelial Cells

ress in Molecular Biology and Translational Science, Volume 116 # 2013 Elsevier Inc.N 1877-1173 All rights reserved.://dx.doi.org/10.1016/B978-0-12-394311-8.00001-7

4

2.
Cadherin-Mediated Cell–Cell Adhesion and the Function of Polarity Proteins
in Apical–Basal Cell Polarity

7

3.
Other Functions of E-Cadherin, Catenins, and “Polarity Protein” Complexes
in Maintaining Epithelial Homeostasis

11

4.

Cadherin, Catenins, and the Origins of Epithelial Polarity

13

Acknowledgments

18

References
18
Abstract

A simple epithelium is the building block of all metazoans and a multicellular stage ofa nonmetazoan. It comprises a closed monolayer of quiescent cells that surround aluminal space. Cells are held together by cell–cell adhesion complexes and surroundedby extracellular matrix. These extracellular contacts are required for the formation of apolarized organization of plasma membrane proteins that regulate the directionalabsorption and secretion of ions, proteins, and other solutes. While advances have beenmade in understanding how proteins are sorted to different plasma membranedomains, less is known about how cell–cell adhesion is regulated and linked to thedevelopment of epithelial cell polarity and regulation of homeostasis.

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http://dx.doi.org/10.1016/B978-0-12-394311-8.00001-7

4 W. James Nelson et al.

1. INTRODUCTION: THE BASIC DESIGN OF POLARIZEDEPITHELIAL CELLS

A fundamental characteristic of simple epithelia is that they form a

two-dimensional sheet of structurally and functionally polarized cells that

is often organized into a three-dimensional tube (Fig. 1.1). The cells are sur-

rounded by extracellular matrix (ECM) and held together by adhesive struc-

tures that include tight junctions (TJ, called septate junctions in Drosophila),

the adherens junction (AJ), desmosomes, and several additional adhesion

complexes ( JAM, nectins).1 A simple epithelial tube separates the organism

into discrete compartments—generally, a specialized internal compartment

separated and protected from the outside environment by the epithelium2—

and regulates the exchange of nutrients, solutes, and waste between these

two compartments thereby maintaining tissue architecture (reviewed in

Ref. 3).

MammalsInsectsEarthworm

Na+

Na+

Na+

Na+K+

K+

K+

ATP

K+

2Cl-

Cl-

Crustaceans

Multicellularity-formation of a cavity(structural and functional polarity)

Exchange of fluids, ions, solutes, and wastebetween biological compartments

Outside

AJC

Inside

Figure 1.1 Functional Organization of a Generic Polarized Epithelium. Epithelial cells inmost metazoans are organized into a closed monolayer that surrounds a luminal space.Different plasma membrane surfaces (apical and basolateral) face different biologicalcompartments (depicted as “inside” and “outside”) separated by the epithelium. Eachplasma membrane domain contains different ion channels (e.g., Kþ- and Cl�-channels),transporters (e.g., Na-K-2Cl-cotransporter), and pumps (e.g., Naþ/Kþ-ATPase) that regu-late ion and solute exchange between the two biological compartments. The cells areheld together by an Apical Junctional Complex (AJC) that includes the tight junction,which regulates the paracellular flow of ions (e.g., Naþ) between the cells (dotted line).

5Roles of Cadherins and Catenins in Cell�Cell Adhesion and Epithelial Cell Polarity

Each cell within a simple epithelium is polarized, with structurally and

functionally distinct plasma membrane domains that face the two compart-

ments separated by the epithelium (Fig. 1.1). The apical membrane domain

faces the luminal surface—topologically the outsideof the organism—and the

basal and lateral (basolateral)membranes face the inner surface comprising the

serosa and interstitium.4 Each membrane domain has different membrane

proteins that enable vectorial transport of ions and solutes across the epithe-

lium (Fig. 1.1).5,6

The distribution ofmembrane proteins between the apical and basolateral

membrane domains relies upon correct sorting of proteins to each plasma

membrane domain (Fig. 1.2). A major site for sorting newly synthesized

Basolateral

Protein/vesiclesorting

TJ

Vesicle fusionExocyst

t-SNARE

v-SNARE

Vesicletethering

Vesiclefusion

Apical

Figure 1.2 Protein sorting in a generic polarized epithelium. Each cell within an epithe-lial tube has apical and basolateral plasma membrane domains, which face differentbiological compartments and have different membrane proteins (see Fig. 1.1). Newlysynthesized apical and basolateral proteins are sorted from each other on the exocyticpathway, primarily in the late Golgi complex (trans-Golgi network), and targeted in ves-icles to the correct plasma membrane domain. At the plasma membrane, vesicle fusionis regulated by the Exocyst (a vesicle tethering complex) and the SNARE complex (ves-icle fusion complex). Proteins may also be sorted in the endocytic pathway (not shown).


apical and basolateral membrane proteins is the Trans-Golgi Complex

(TGN) (reviewed in Refs. 5–7), but additional sorting events between

the TGN and plasma membrane domains8 and different membrane domains

(transcytosis)9 occur in the endocytic pathway. The docking and fusion of

vesicles carrying sorted cargo proteins with the correct membrane domain

require specific vesicle tethering complexes (e.g., the exocyst), Rab

GTPases, and SNARE complexes localized to the apical and basolateral

membrane (Fig. 1.2) (reviewed in Refs. 5,6). The distributions of proteins

at the apical or basolateral membrane domain are maintained by the TJ,

which provides a molecular fence at the boundary between the apical and

basal–lateral membrane domains (reviewed in Ref. 10). A cytoplasmic scaf-

fold complex of ankyrin–spectrin binds classes of membrane proteins that

include ion transporters and channels and retains them on the basal–lateral

membrane (reviewed in Ref. 11).

The actin, microtubule, and intermediate filament cytoskeletons in

polarized epithelial cells have organizations different from those in other cell

types. Actin filaments are organized as bundles within microvilli present on

the apical membrane, as a ring of filament bundles circumscribing the apex

of the lateral membrane often in association with the apical junctional com-

plexes (AJC, comprising TJ and the AJ), and as dense networks lining the

lateral and basal membranes (cortical cytoskeleton). In many epithelia,

microtubules are prominently organized in bundles parallel to the lateral

membrane with their minus-ends oriented toward the apical membrane

and plus-ends toward the basal membrane, and as networks of filaments

of mixed polarity underneath the apical and basal membranes. Intermediate

filaments (usually members of the cytokeratin family) are organized as a

structural continuum interlinking desmosomes across the cell.12

The structural integrity and functional polarity of epithelial tubes require

both cell–cell adhesion and cell–ECM adhesion, which provide important

physical and signaling cues for the initiation of cell polarization. Of the

cell–cell adhesion complexes, evidence indicates that the cadherin superfam-

ily plays an important role. For example, genetic deletion or mutations in

E-cadherin disrupt the formation of the first organized tissue structures in

the early mammalian embryo—the trophectoderm of the preimplantation

mouse embryo13—and the epidermis of the Drosophila embryo following

cellularization.14 siRNA-mediated knockdown of E-cadherin in MDCK

cells in tissue culture, which forms polarized monolayers of cells in two-

and three-dimensional configurations, also inhibits the establishment of cell

polarity.15 Other proteins are involved in cell–cell adhesion, including


members of the Ig superfamily (JAM1-3 andnectin), and it has been suggested

that nectins initiate adhesion between cells upstream of cadherin-mediated

cell–cell adhesion, and that both nectins and cadherins combine to sort cells

into different arrangements16,17 (see also Chapter 19).

Cadherins form extracellular contacts with cadherins on opposing cells

through their N-terminal EC1 domain.18 The cytoplasmic domain interacts

with several proteins that either control cadherin turnover (p120 catenin,

hakai) or link the complex, directly or indirectly, to the actin cytoskeleton

(b-catenin and a-catenin).19 Studies in epithelial tissues have shown thatmutations of b-catenin or a-catenin, like that of E-cadherin, result in dis-ruption of tissue organization20: for example, mutations of b-catenin ora-catenin in theDrosophila follicle cell epithelium result in defects in overallpolarized cell morphology and the organization of the apical and basolateral

plasma membrane domains.21,22 Although downstream interaction of the

cadherin–catenin complex with the actin cytoskeleton is complicated and

not completely understood,19,23 cadherin engagement locally regulates

the activity and localization of Rho family GTPases,24 which regulate actin

organization and function.25

2. CADHERIN-MEDIATED CELL–CELL ADHESIONAND THE FUNCTION OF POLARITY PROTEINS

IN APICAL–BASAL CELL POLARITY

How cells respond to cadherin-mediated cell–cell contacts to initiate

the formation of functionally different plasmamembrane domains is not well

understood. The initial establishment of cell surface polarity may be con-

trolled at the plasma membrane by the position of the adhesive complex

formed at cell–cell contacts and by the rapid organization of microtubules

and the exocytic machinery that specifies the delivery of the correct set of

transport vesicles to that site (Fig. 1.3). Basal–lateral protein accumulation

at nascent cell–cell contacts in MDCK tissue culture cells requires microtu-

bules,26,27 the exocyst vesicle tethering complex, and the vesicle fusion

t-SNAREsyntaxin4 (Figs. 1.2 and1.3).27Microtubulesmay attach indirectly

to the cadherin–catenin complex through interactions with the dynactin

complex28,29 and through interactions between p120catenin and kinesin 1.30

Mechanisms involved in localizing t-SNAREs to initial cell–cell contacts

remain poorly understood. However, the exocyst is in a complex with

E-cadherin and nectin, suggesting a direct recruitment of the exocyst to

membrane sites of E-cadherin adhesion.31 Indeed, the exocyst is recruited

PMVesicle-microtubules

[transport]

Golgi-endosome[sorting]

Targeting patch(exocyst; tSNAREs)[capture – sorting]

ExtracellularCue

DeliverySortingFidelity

Efficiency Sorting

Figure 1.3 Mechanisms Involved in Protein Trafficking to Cell–Cell Contacts. An extra-cellular cue (cadherin-mediated cell–cell adhesion) initiates the assembly of a TargetingPatch (the exocyst, t-SNAREs) at sites of cell–cell contact, and the orientation of themicrotubule cytoskeleton. In the Golgi complex and endosomes, basolateral membraneproteins are sorted into vesicles that are efficiently delivered along microtubules to theplasma membrane. At the plasma membrane, the targeting patch specifies the correctdelivery and fusion of vesicles containing basolateral membrane proteins.


to the plasma membrane and sites of cell-cell contact upon cadherin-

mediated cell–cell adhesion,31,32 and knockdown of Ral GTPases, which

regulate exocyst function, affect TJ assembly and function.33 The exocyst

also regulates the distribution of polarity protein complexes (see Section 3

for details). Loss-of-function mutations in the Exo84 exocyst subunit in

Drosophila result in loss of Crumbs and the PAR complex from the AJC

and their localization along the lateral membrane, and an overall decrease

in the columnar morphology of cells.34

A distinctive feature of polarized epithelia is the spatial distribution of

evolutionarily conserved polarity protein complexes around the AJC

(Fig. 1.4).35,36 These complexes can have subtly different localizations in dif-

ferent contexts, but in general the Crumbs complex is located at the apical

side of the AJC37 and at the primary cilium38; the PAR complex is localized

close to the AJC39,40 and at the primary cilium (Fig. 1.4)41; and the Scribble

complex is localized on the lateral membrane below the AJC.37,40 Together,

these polarity proteins regulate the organization of the apical (Crumbs [Crb],

Stardust [Std], PAR complex) and basolateral membrane domain (Lethal

giant larvae [Lgl], Discs large [Dlg], Scribble), respectively, in many polar-

ized epithelial cells (Fig. 1.4).35,37 For example, loss of expression of Crumbs

Apicalmembrane

Basal–Lateralmembrane

Extracellular matrix

Basal–lateralmembrane

Scribble

LGLDLG

PALS

PATJ

PAR3

aPKC PAR6

PAR1

Apicalmembrane

Crumbs3

Crumbs

PAR3/6

dynein

CrumbsmRNA

Microtubules

AJCAJC

SdtPAR3

Golgi

Primarycilium Polarity complexes

Figure 1.4 Distribution of “polarity protein” complexes in a generic polarized epithe-lium. Polarized epithelial cells are attached to each other by an apical junctional com-plex (AJC) and adhere to the underlying extracellular matrix. Each cell has a singleprimary cilium on the apical plasma membrane. Different “polarity protein” complexes(Crumbs, PAR, Scribble) are localized around the AJC, and regulate the organization ofthe apical (Crumbs) and basolateral (Scribble) plasma membrane domains. The Crumbsand Scribble complexes antagonize each other's activities. The localization of somecomponents of the “polarity protein” complexes is regulated by cell–cell adhesion(see text) and by microtubule-dependent trafficking of mRNAs to the apical cytoplasm.


results in disruption of the apical membrane domain and cell polarity,

whereas overexpression of Crumbs leads to the expansion of the apical

membrane at the expense of the (baso)lateral membrane domain; expansion

of the apical membrane domain in wild-type conditions is inhibited by the

(baso)lateral complex of Dlg, Scribble, Lgl, and PAR-1. Thus, the functions

of apical and (baso)lateral polarity protein complexes are mutually antago-

nistic (Fig. 1.4).37,40

Studies of the ovariole follicle cell epithelium inDrosophila reveal that the

DE-cadherin–catenin complex is required for the maintenance of follicle

cell polarity.42 Loss-of-functionmutations ofDE-cadherin,43 arm/b-catenin,37

ora-catenin22 disrupt follicle cellmorphology, the (baso)lateral organizationof


the a-spectrin/actin cytoskeleton and Dlg, and the apical organization ofCrumbs and the cortical cytoskeleton of bH-spectrin. Some of these defectsappear to be due to inhibition of vesicle docking with the plasma mem-

brane,22 supporting a role for the cadherin–catenin complex and down-

stream effectors in vesicle trafficking.27 Interestingly, the defects induced

by a-catenin mutants can be partially ameliorated by reducing the activityof the WAVE-Arp2/3 complex,22 supporting a role of a-catenin and theArp2/3 complex in regulating actin assembly44,45 and, possibly, cell surface

levels of E-cadherin.46,47

Several mechanisms regulate the different distributions of these “polarity

protein” complexes. The PAR complex localizes to nascent epithelial

cell–cell contacts48 through binding to the adhesion proteins JAM-A,49

nectin50, and b-catenin.51 Analysis of cadherin–catenin and PAR-3(bazooka) localization during initial adhesions between epidermal cells in

the Drosophila embryo52 indicate that PAR-3 might be involved in proper

positioning of the nascent AJs. Early recruitment of the PAR complex to

cell–cell contacts establishes the location of the PAR complex at the AJC

between the forming apical (Crumbs complex) and basal–lateral (Scribble

complex) membrane domains. PAR4/LKB1 also closely colocalizes with

E-cadherin.53 PAR4/LKB1 may locally regulate activation of PAR1 and

MARKs, and thereby the organization of microtubules and the delivery

of vesicles to the plasma membrane.54–56

Positioning the Crumbs complex close to the PAR complex in the

region of the Apical junctional complex (Fig. 1.4) may be mediated by bind-

ing between different PDZ domain-containing proteins in the PAR com-

plex (PAR3 and PAR6) and Crumbs complex (PALS1 and PATJ).57,58 In

addition, studies in Drosophila indicate that Crumbs mRNA is restricted to

the apical domain of epithelial cells by a dynein-dependent basal to apical

transport along microtubules,59 which could result in its localized translation

in the apical cytoplasm; a similar mechanism may be important in apical

localization of PAR3/bazooka60 and Stardust (Sdt, the Drosophila homolog

of mammalian PALS1) (Fig. 1.4).61

Despite strong genetic evidence of the importance of these polarity pro-

tein complexes in apical–basal polarity of epithelial cells, their functions

remain poorly understood. The Crumbs complex (Crumbs, PALS1, and

PATJ) is required for the formation and maintenance of the TJ.10,62 A recent

study in mammalian tissue culture cells showed that PALS1 and PATJ bind a

Cdc42-GAP called Rich1 (RhoGap-interacting with CIP4 homologues

protein-1) and the scaffold protein AMOT (angiomotin), which together


control Cdc42-dependent endocytosis of PALS1, PAR3 and overall TJ per-

meability.63 Significantly, a separate study in Drosophila reported that dele-

tion of either aPKC or PAR6 resulted in discontinuities in the AJC, and the

appearance of E-cadherin further down the lateral membrane.47 Similar

phenotypes were observed by deleting Wasp, Arp2/3, or dynamin.47

One possible mechanism linking these phenotypes could be a role for

actin-mediated endocytosis in controlling the proper level and localization

of E-cadherin and signaling activities of polarity protein complexes at the

AJC.63This is further supported by theobservation that defective endocytosis

of Crumbs leads to expansion of the apical domain, a phenotype associated

with “excess” Crumbs activity.64

Scribble is localized basal to the AJC along the lateral membrane domain.

Its function is poorly understood. One possibility is that Scribble locally reg-

ulates Ca2þ-dependent exocytosis in a complex with bPIX and GIT1.65

Scribble also binds PAR-1 and might regulate the localization of the

PAR-1 kinase activity, and thereby exclude the PAR-3 complex.66 Lgl is

in a complex with the basal–lateral t-SNARE syntaxin 4 indicating that it

too might be involved in regulating vesicle trafficking.67 This is supported

by the observation that depletion of Lgl results in inhibition of some protein

delivery to the plasma membrane in neurons, including N-cadherin.68

However, Lgl also binds myosin II69 and the PAR-6/aPKC complex70

and may be involved in the localization of these proteins to the lateral

membrane.

3. OTHER FUNCTIONS OF E-CADHERIN, CATENINS, AND“POLARITY PROTEIN” COMPLEXES IN MAINTAINING

EPITHELIAL HOMEOSTASIS

Core components of the cadherin�catenin cell�cell adhesion com-plex are tumor suppressors (E-cadherin,71,72 a-catenin73) and an oncogene(b-catenin74) and loss of function of the cadherin–catenin complex leads toincreased cell proliferation, cell migration, and a general disruption of epi-

thelial homeostasis.20,75–77 Normally, cell growth in epithelial sheets is

suppressed by contact inhibition78, which involves cadherin-mediated

cell�cell adhesion.79,80 In addition, b-catenin and a-catenin regulate cellcycle progression: b-catenin is a Wnt pathway coactivator of genes thatinduce cell cycle progression (cyclin D1, c-myc),77,81 and a-catenin regu-lates the Hippo pathway by sequestering in the cytoplasm the transcriptional

coactivator Yki/Yap-Taz, which also drives the expression of genes that


promote cell proliferation.77,80,82,83 Another cell�cell junction associatedprotein, ZONAB, a Y-box transcription factor, binds to the TJ scaffold pro-

tein ZO-184 and interacts with the cell cycle regulator CDK4,85 which in

turn controls expression of cyclin D1 and PCNA.

Polarity protein complexes not only regulate the polarized organization

of cells but also control cell proliferation, which likely contributes to the loss

of both cell polarity and cell proliferation control when these proteins are

mutated or deleted. For example, Scribble86 andDlg87 contain a domain that

is required for cell polarity (LLR domain), and another (PDZ domain) that

controls cell proliferation. Significantly, the cell proliferation defect induced

by deletion of the PDZ domain of Scribble can be rescued by overexpression

of the LRR domain.86 Thus, Scribble regulation of cell proliferation and cell

polarity may be linked, althoughmore work is needed to fully define the role

of Scribble in these pathways.

The effects of depletion of Scribble on cell polarity and cell proliferation

have also been tested in three-dimensional acini formed by MCF10A mam-

mary epithelial cells. Depletion of Scribble has a modest effect on

apical–basal polarity, but the luminal space of the acini fills with cells.88

Luminal filling is due to a decrease in apoptosis, rather than an increase in

cell proliferation, and apoptosis is indeed required to clear the luminal space

of cells in this model system.89 As noted above, Scribble forms a complex

with bPIX/GIT1, which can activate Rac1; in turn, activated Rac1 inducesapoptosis by activating JNK, and in the absence of Scribble (or bPIX) thisdoes not occur, resulting in overgrowth of cells.88

A genetic screen inDrosophila for mutations that enhanced tumorigenesis

caused by loss of Dlg expression identified the serine/threonine kinase

Warts.90 In Drosophila, Warts is a downstream component of the Hippo sig-

naling pathway that regulates cell proliferation (see above). Interestingly, the

mammalian homologs of Hippo (Mst1 and Mst2) and Warts (Lats1 and

Lats2) are also tumor suppressors and loss of their expression is linked to

highly aggressive breast tumors.91 As noted above, downstream targets of

Warts regulate cell cycle progression and apoptosis.90,91 These results indi-

cate that Dlg may also be involved in controlling cell cycle progression and

apoptosis, but further studies are needed to define how it is linked to the

Hippo–Warts signaling pathway.

In conclusion, the cadherin�catenin complex and polarity proteincomplexes not only regulate cell–cell adhesion and cell polarity, but also the

control of cell proliferation in maintaining epithelial homeostasis. Thus, dis-

ruption of cell�cell interactions, cellular organization and cell proliferation


that is often found in cancers and other diseases may be directly related to loss

of function of protein components of these complexes.

4. CADHERIN, CATENINS, AND THE ORIGINS OFEPITHELIAL POLARITY

Given the requirement of the cadherin�catenin complex in the orga-nization of polarized epithelial cells from mammals to Drosophila raises the

question of whether the appearance of cadherins and catenins in evolution

coincide with the development of multicellularity, and with the organiza-

tion of cells into functionally polarized epithelia92. Metazoans belong to

the Unikonta, a group that includes fungi and social amoebae that can also

have multicellular stages. However, it is generally thought that animals,

fungi, and social amoebae evolved multicellularity independently, and that

formation of an epithelium is a unique feature of animals.93–95 Bilateria

evolved additional cell types, such as mesenchymal cells that migrate to dif-

ferent sites in the body cavity where they contribute to the formation of sec-

ondary epithelia. This enabled a further diversification in the organization

and distribution of functionally different epithelial tissues and organs.96

Theevolutionof cadherins is discussed indetail inChapter 4, but it is nota-

ble that cadherins have only been found inmetazoans and a close single-celled

relative, the Choanoflagellates,92 although Choanoflagellate cadherin lacks

the catenin-binding domain found in higher metazoan cadherins and has

not yet been shown to regulate cell–cell adhesion.However, a similar analysis

of catenins, particularly a-catenin, reveals that homologues are found in thegenomes of some nonmetazoans.97 a-Catenin is structurally similar to vin-culin, and all metazoans examined have at least one a-catenin orthologueand one clear vinculin orthologue.97 These metazoans include sponge

(Amphimedon queenslandica), cniderians (Hydra magnipapillate, Nematostella

vectensis), and bilaterians (Drosophilamelanogaster,Homo sapiens). The sequence

identity of the a-catenin orthologues compared to the human aE-cateninranges from �60% (D. melanogaster) to


characterization ofDda-catenin/vinculin show that it is a monomer that bindsand bundles F-actin constitutively, properties that are different from those of

mouse a-catenin or vinculin: mouse a-catenin is either a monomer that isconformationally inhibited or an activated homodimer that binds F-actin

strongly), and vinculin is a monomer that is conformationally inhibited, and

must also be activated, for example by talin, to bind F-actin. Interestingly,

Dda-catenin/vinculin also differs from the Caenorhabditis elegans a-catenin,called HMP-1 (see also Chapter 11). HMP-1 is a monomer that is

conformationally inactive and does not bind F-actin in vitro, although studies

in vivo indicate that HMP-1 becomes activated and that both the b-catenin-and actin-binding sites are required for normal development.98

Unlike vinculin, the head and tail domains of Dda-catenin/vinculin donot interact and the protein does not colocalize with talin at cell–substrate

adhesion sites in single cells. In addition, depletion of Dda-catenin does notaffect cell–substrate adhesion. Dda-catenin/vinculin binds Ddb-catenin(also called Aardvark99) and, remarkably, is able to bind mouse b-catenin,indicating evolutionary conservation of binding sites and structure. Based

on these properties the Dda-catenin/vinculin likely encodes an a-cateninorthologue, indicating that vinculin arose later during evolution.97

D. discoideum expresses a b-catenin-related protein called Aardvark.99

Both Aardvark and mammalian b-catenin contain Armadillo (Arm) repeats.Aardvark has 9 Arm repeats, compared to 12 in metazoan b-catenins. TheArm repeats of b-catenin fold to form a positively-charged groove and a sim-ilar feature is predicted in Aardvark. E-cadherin and TCF/LEF transcription

factors bind along this groove in mammalian b-catenin, but none of theseproteins are expressed in Dictyostelium and it is unknown whether there

are additional binding partners. Aardvark and mammalian b-catenin sharea highly conserved a-catenin-binding helix at the N-terminus of the Armrepeat domain. In contrast to these similarities, Aardvark lacks sequences

in the C-terminal tail of b-catenin that are important for the transcriptionalactivity of b-catenin in Wnt signaling, and in the N-terminal region ofb-catenin that contains GSK-3b phosphorylation sites important fortargeting b-catenin for degradation. Thus, Aardvark does not have sequencefeatures necessary for Wnt signal transduction pathway, and several other

key Wnt signaling proteins are absent in D. discoideum.97

Although D. discoideum does not express a cadherin homologue, the

a-catenin and b-catenin orthologues play critical roles in the muticellularstage of the D. discoideum life cycle. In the presence of plentiful food (bac-

teria), D. discoideum is a single-cell amoeba. However, when food becomes


scarce the amoebae aggregate, form a motile multicellular slug, undergo cul-

mination, and develop into a fruiting body.100 The fruiting body comprises a

rigid stalk that supports a collection of spores. Cells at the tip of the culmi-

nant form a ring surrounding the stalk tube, which contains cellulose and the

ECM proteins EcmA/B that provide mechanical integrity to the stalk.101

Confocal microscopy showed that the tip cells comprise an organized

monolayer of columnar cells surrounding the stalk (Fig. 1.5A). This organi-

zation is reminiscent of a simple epithelium surrounding a luminal space

found in metazoans. Indeed, similar to metazoan epithelia, the centrosomes

and Golgi localize to the stalk side of the nuclei, and the transmembrane pro-

tein cellulose synthase is localized to a plasma membrane domain adjacent to

the stalk. Protein trafficking pathways that specify polarized protein distribu-

tions are unknown in D. discoideum. However, Sec15, a component of the

Exocyst complex involved in polarized exocytosis in diverse systems, local-

izes at the plasma membrane adjacent to the stalk tube; this is reminiscent of

exocyst localization in polarizedmammalian epithelial cells. Actin is localized

at all plasma membrane domains but is enriched apically with myosin II,

and the microtubules have a polarized organization. These characteristics

indicate that the cells form a bona fide epithelium (Fig. 1.5A and B).97

“Basolateral”membrane

Stalk tube

A B

MTs?Exocyst

Cellulosesynthase Myosin II

Dda-cateninAardvark

Cortexillin IIQGAP

F-actin

“Apical” membrane

Figure 1.5 A polarized epithelium in the nonmetazoan Dictyostelium discoideum. (A) Aconfocal immunofluorescence section through the tip of the fruiting body stained for:F-actin (green), Dda-catenin, (red), nuclei (blue), and microtubules (magenta). The cellsare organized into a single layer (the Tip Epithelium) surrounding the stalk tube. (B) Sche-matic representation of the distribution of cytoskeleton (Dda-catenin, Ddb-catenin/Aardvark, F-actin, myosin II, IQGPA, cortexillin I, micotubules/MTs), a plasma membraneprotein (cellulose synthase), and components of the secretory pathway (Golgi complex,exocyst). For details about the staining and organization of proteins in the tip epithe-lium, see Refs. 97,102.


Expression of Aardvark/b-catenin and a-catenin is up-regulated shortlyafter aggregation of the amoebae, and both proteins are present during all

stages of culmination. Significantly, a-catenin colocalizes at cell–cell con-tacts between tip epithelial cells and is generally excluded from the mem-

branes facing the stalk tube and the base (Fig. 1.5A and B); this

distribution is similar to that in animal polarized epithelial cells in which

cell–cell adhesion involves cadherins. As Aardvark/b-catenin and a-cateninform a complex, it is assumed that Aardvark/b-catenin colocalizes on thelateral membrane as well. Knockout of Aardvark/b-catenin results in lossof lateral membrane localization of a-catenin. Although the membrane pro-tein binding site(s) for Aardvark/b-catenin and a-catenin are unknown,these results indicate that the binding hierarchy of membrane protein

X—Aardvark/b-catenin—a-catenin in Dictyostelium may be similar to thatof the cadherin–catenin complex in metazoan epithelial cells.

Knockout of Aardvark/b-catenin or knockdown of a-catenin appears tohave no effect on the migration or aggregation of amoebae, or on slug for-

mation and migration. However, multicellular development is arrested at

those early stages. Cells that would normally contribute to the formation

of the tip epithelium are disorganized. The stalk and tip epithelium are

absent in severe Dda-catenin knockdowns, but are present, although disor-ganized, in Aardvark knockouts and mild Dda-catenin knockdowns.102

Furthermore, the distributions of the Golgi and centrosomes are not polar-

ized, and the transmembrane protein cellulose synthase is mislocalized intra-

cellularly, which explains the absence of extracellular cellulose.97 Therefore,

the polarized organization of cells in the tip epithelium requires both Aard-

vark/b-catenin and a-catenin, similar to the requirement of catenins for theorganization of epithelia in animals.

Themolecular interactions required for organizing the tip epithelium are

poorly understood. Proteomic analysis of b-catenin/Aardvark–a-catenincomplexes revealed a downstream complex of IQGAP1 and cortexillin I that

spatially regulates the distribution to myosin II (Fig. 1.5B).102 IQGAP1 and

cortexillin I form a complex.103,104 Unlike mammalian IQGAP1, the

DdIQGAP1 lacks an actin-binding domain, suggesting that the actin-binding

module of cortexillin I confers this activity in the complex.102 IQGAP1 and

cortexillin I colocalize with Aardvark/b-catenin and a-catenin on the lateralmembrane between cells, but both proteins are absent from the apical mem-

branedomain adjacent to the stalk tube (Fig. 1.5B).Myosin II colocalizeswith

actin at the membrane facing the stalk tube, and forms a continuous ring

around the cell, very similar to the actomyosin ring found in metazoan


epithelial tubes;myosin II is less concentrated on the basolateral plasmamem-

brane surface that contains Aardvark/b-catenin, a-catenin, IQGAP1, andcortexillin I (Fig. 1.5B).

Significantly, deletion of Aardvark/b-catenin or a-catenin results indisorganized localizations of IQGAP1, cortexillin I and myosin II, as tip epi-

thelium cells lose polarity and monolayer organization. Knockouts of either

IQGAP1 or cortexillin I result in a multilayered epithelium in which cells

are still polarized, and loss of myosin II and the actomyosin ring from the

plasma membrane adjacent to the stalk tube. Disruption of the actomyosin

ring results in a stalk tube that is�2�wider than in wild-type culminants.102Together these results indicate that Aardvark/b-catenin and a-catenin inter-act with and regulate the distribution of the IQGAP1/cortexillin I complex.

In turn, the IQGAP1/cortexillin I complex excludes myosin II from the

basolateral cortex and promotes accumulation of actomyosin on the mem-

brane facing the stack tube.102 The mechanisms involved in the exclusion of

myosin II from the lateral membrane are unknown. Nevertheless, these

results reveal that apical localization of myosin II is a conserved morphoge-

netic mechanism from nonmetazoans to vertebrates, and identify a hierarchy

of proteins that regulate the polarity and organization of an epithelial tube in

a simple model organism (Fig. 1.6).

The presence of a polarized epithelium in the nonmetazoanD. discoideum

demonstrates that an epithelial tissue is not a unique feature ofmetazoans, and

that catenins are an ancient protein module involved in the formation of

membrane domains and epithelial polarity (Fig. 1.6). Thus, metazoans and

social amoebae may have evolved from an ancestor that spent a portion of

Dictyostelium

Cadherin

Actomyosincontraction

b-Catenin

Actindynamics

a-Catenin

Mammals

RacGTPases

RhoGTPase

Cell shape change

Cellpolarity

Cellpolarity

Cell–CellAdhesion

Cell-shapechange

Aardvark

Myosin II (actin)

IQGAP I Cortexillin I(actin)

Dda-catenin

Figure 1.6 Comparison of proteins and pathways downstream of the (cadherin)–catenin complex, and their functional outcomes. For details, see text.


its life cycle in a multicellular state and possessed the molecular machinery

necessary for converting cell–cell interactions into the formation of a func-

tionally and structurally polarized epithelial tissue.95 Interestingly, none of

the genes encoding polarity proteins are present in the Dictyostelium

genome.97 This raises the possibility that polarity proteins may have evolved

separately, perhapswith the appearance of cadherins, to regulate the increased

complexity of tissue organization in metazoans.95

ACKNOWLEDGMENTSSupported by NIH grants GM35527 (W. J. N.) and GM56169 (W. I. W.).

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Roles of Cadherins and Catenins in Cell-Cell Adhesion and Epithelial Cell PolarityIntroduction: The Basic Design of Polarized Epithelial CellsCadherin-Mediated Cell-Cell Adhesion and the Function of Polarity Proteins in Apical-Basal Cell PolarityOther Functions of E-Cadherin, Catenins, and ``Polarity Protein´´ Complexes in Maintaining Epithelial HomeostasisCadherin, Catenins, and the Origins of Epithelial PolarityAcknowledgmentsReferences

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RolesofCadherinsandCateninsin Cell Adhesion and Epithelial ...download.xuebalib.com/5id6COUoQLjc.pdf · Introduction: The Basic Design of Polarized Epithelial Cells 4 2. Cadherin-Mediated