E-cadherin roles in animal biology: A perspective on thyroid hormone-influence
Izaguirre and Casco Cell Communication and Signaling
E-cadherin roles in animal biology: A perspective on thyroid hormone-influence
María Fernanda Izaguirre 0
Victor Hugo Casco 0
0 Laboratorio de Microscopia Aplicada a Estudios Moleculares y Celulares, Facultad de Ingeniería (Bioingeniería-Bioinformática), Universidad Nacional de Entre Ríos , Ruta 11, Km 10, Oro Verde, Entre Ríos , Argentina
The establishment, remodeling and maintenance of tissular architecture during animal development, and even across juvenile to adult life, are deeply regulated by a delicate interplay of extracellular signals, cell membrane receptors and intracellular signal messengers. It is well known that cell adhesion molecules (cell-cell and cellextracellular matrix) play a critical role in these processes. Particularly, adherens junctions (AJs) mediated by Ecadherin and catenins determine cell-cell contact survival and epithelia function. Consequently, this review seeks to encompass the complex and prolific knowledge about E-cadherin roles during physiological and pathological states, particularly focusing on the influence exerted by the thyroid hormone (TH).
E-cadherin; Adherens junction; Epithelia; Development; Evolution; Thyroid hormones
Since the early 70s, prolific and significant research and
hypotheses subscribe to the theory that unicellular to
multicellular transition has occurred more than once
during evolution through different genetic mechanisms for
each kingdom in the tree of life. Particularly, cadherin and
integrin cell adhesion molecules played a crucial role in
metazoan transition [78, 171].
In addition, the interpretation of the cellular role of
cadherin has changed over time, from a static membrane
protein involved in cell-cell adhesion mechanic events to a
membrane receptor involved in very dynamic intracellular
signal transductions. These processes would be mediated
not only from cell-cell junction platforms, but also from
single receptors [29, 189, 216].
In different physiological contexts during development
and adulthood, this adhesion is highly plastic, suffering
remodeling due to numerous and complex signaling
cascades finely coordinated in time and space. Thus, in
pathological states such as cancer, the configuration of
this adhesion is altered by genetic and epigenetic
changes, resulting in modifications in the signaling
pathways, loss of inhibition by contact, cell migration,
and altered stromal interactions. A key group of these
cell-cell adhesion molecules is the superfamily of
cadherins, whose prototypical member is E-cadherin. This
molecule was found for the first time in epithelial tissues
[177, 215] and has been characterized as a potent
suppressor of invasion and metastasis in studies dating back
to 1990 (reviewed by ). E-cadherin plays a key role
in determining cell polarity and differentiation, and
thereby in the establisment and maintainance of tissue
homeostasis. It is also important during development
and during the whole life cycle of pluricelular organisms,
In this work, four major aspects bring E-cadherin into
focus. First, epithelia are composed of cell phenotypes
which exhibit the maximum polarity and whose epithelial
identity is primarily specified by E-cadherin. Second,
Ecadherin is involved in numerous processes such as, cell
phenotype selection and migration, and morphogenetic
movements occurring during metazoan development [26,
192, 193, 196]. Third, epithelia are usually located in direct
contact with mutagenic and/or carcinogenic agents, so in
men, 85–90 % of the cases can be attributed to epithelial
cancers. Lastly, the complexity of in vivo animal studies
has partly concealed the full spectrum of E-cadherin
functions. Owing to the latter, the work-goal focuses on
Ecadherin control mediated by thyroid hormones in a
scarcely studied physio-pathological scenario.
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E-cadherin function during metazoan development
Cadherins are a huge family of Ca2+-dependent cell
surface adhesion glycoproteins, which are differentially
expressed in tissues and ontogeny among broad groups of
organisms, from unicellular choanoflagellates to
invertebrates and all vertebrates classes. Therefore, cadherin
evolution has special relevance for understanding metazoan
origins [2, 62, 66, 77, 78, 80, 140, 143, 171, 192, 196].
Classical cadherins, like E(epithelial)-cadherin, bind to
βcatenin via the cytoplasmic domain (CD) and promote
cellcell adhesion  or are rapidly degraded [32, 76, 86]. As
development progresses, cadherins establish and maintain
AJs through adaptor proteins to the cytoskeleton [63, 64,
129, 141]. These complex structural units are called
cadhesomes , and act integrating signals from extracellular
and intracellular environments [19, 62, 85–87, 138]. In
vertebrates, E-cadherin mRNA and protein are maternally
expressed, beginning their zygotic expression from 2-cell
embryo or gastrulation [8, 9, 34, 91, 114, 191]. Although
Ecadherin is principally expressed in the epidermal ectoderm
, it has also been found in derivatives of
neuroectoderm, mesoderm and endoderm [39, 85, 87]. In some
species, embrionary E-cadherin is necessary for 8-cell stage
compaction, for trophectoderm expansion [7, 108], and for
maintaining epiboly integrity . Later during
development, E-cadherin contributes to the morphogenesis of
endodermal and neuroectodermal derivates , and digestive
tract, kidney and skin remodeling [85–87, 179, 197]. In
invertebrates, a vertebrate E-cadherin homolog is critical for
cell rearrangement  and packing geometry .
Some studies suggest that three modern cadherin families
—lefftyrins, coherins, and hedglings— were present in the
last common ancestor of choanoflagellates and metazoans,
and they may have evolved to diverse metazoan signaling
and adhesion gene families . Several
cadherinanalogous functions have been hypothesized in non
metazoan unicellular lineages in spite of the fact that cadherins
are undocumented in choanoflagellates. These organisms
express members of key cell signaling and adhesion protein
families that were previously thought to be exclusively found
in animals [97, 98]. By studying cell differentiation and
development in some choanoflagellates, it may be possible to
characterize some ancestral functions (bacterial prey
adhesive capture, attachment to environmental substrates,
gamete recognition and hormonal signaling) of proteins that
regulate animal development [46, 47, 98]. Interesting,
numerous studies show interaction processes between bacteria
or yeast and metazoan cadherins promoting host invasion
[17, 36]. In addition, other studies inform that no receptors
or ligands were identified from the nuclear hormone
receptor, WNT and TGF-β signaling pathways . As we will
explain later, the absence of nuclear hormone receptors and
ligands, and molecules involved in Wnt signaling pathways
suggest combined features and roles in a single
moleculetype: the metazoan cadherins.
Taken together, these data and our results on
THdependent E-cadherin control [56, 85], support the idea
that classical cadherins could have emerged in the
premetazoan to metazoan transition to respond to signaling
mediated by nuclear hormone receptors and
cytoskeleton connexions. Indeed, the development of complex
multicellular organisms requires a genetic program
regulated by nuclear hormone receptor signaling and
dynamic cytoskeleton reorganizations.
E-cadherin structure, function and dysfunction
In their mature state, most cadherins have three segments:
the extracellular (EC), trans-membrane(TM) and
cytoplasmic (CD) domains (Fig. 1). The EC domain is mainly
involved in homophilic recognition and Ca2+-dependent
adhesion mechanisms, and it is constituted by a variable
amount of cadherin type-repeats (ECn). Each one has a
βsandwich Ig-like folding that contains conserved
Ca2+-coordinating regions . Each ECn is enumerated from the
outermost N-terminal EC1 to the closest to membrane
EC1 + n. The CD domain exhibits the highest variability
among the cadherin subfamilies [66, 77] and binds to
different intracellular proteins giving both functional
connection to the cytoskeleton  and diversity [66, 140].
E-cadherin function control via EC
The mature classical E-cadherin is a single-pass
transmembrane glycoprotein with five ectodomains (EC1–5),
each made up of ~110 amino acid residues. Their
NH2terminal ectodomain mediates adhesive binding to
cadherins present on the surfaces of neighboring cells. Their
four interdomain junctions are characterized by three
calcium binding sites ─DXD, DRE, and DXNDNAPXF
sequence motifs─ . Cadherin function requires
calcium to rigidify the EC domain [27, 112, 146] and to
stabilize the protein [156, 159] avoiding proteolysis [79,
190], and allowing its proper localization [57, 156, 159].
E-cadherin mediates principally in cell-cell homophilic
interactions through self-recognition of the conserved
histidine-alanine-valine (HAV) sequence within EC1 
(Fig. 1), and a strand-swapping interface. In this surface, a
Tryptophan in position 2 (W2/Trp2) inserts into a
hydrophobic pocket from another cis (from the same cell surface)
or trans (from an adjacent cell) cadherin [100, 111, 182].
Although another cis dimerization has been postulated ,
several models disagree on the roles and numbers of the
inner EC domains involved in cadherin homophilic
interaction [31, 66, 112, 160].
Cleavage of the ~130 amino acids prodomain of
immature cadherin represents the switch from a non adhesive
to the functional form . Even though the specific
Ecadherin endoprotease has not been identified yet ,
Fig. 1 (See legend on next page.)
(See figure on previous page.)
Fig. 1 Structure and regulation of E-cadherin gene and protein. Scheme represents human chromosome-16q22.1 cadherin cluster (CDH1/E-cadherin and
CDH3/P-cadherin locus), and a regulation model both CDH1 locus and protein. CDH1 locus has 16 exons (black bars), cis-regulatory elements (DHSs, vertical
arrows), transcription and translation start sites (small horizontal arrows), several enhancer sequences (green boxes and arrows) ─alternative intron
2independent gene activation in late embryogenesis (alt), specific expression in (brain) or endoderm (enh), or ectoderm/tissues (tse1-4)─, downregulated
sequences (red arrows) ─E-boxes and brain-specific silencer (sil)─, and yolk sac-specific elements outside of intron 2. Locus control region (LCR) could
activate or downregulate gene activity (purple arrow). CpG methylation and E-box-bounded specific repressors (Snail1, slug, E47, δEF1/ZEB1 SIP1/ZEB2) control
the promoter, as well as poly-ADP ribosylation and repressor inhibition (miR-200). MIR and MaLR regulatory-associated repetitive elements (light blue arrow)
were bioinformatically found in introns 2 and 3, and are involved in exonization and increased novo intronic transcription. New transcripts have been revealed
from intron 2-transcription and exon 11 skipping (red cross). In Drosophila melanogaster, CDH1-mRNA translation is suppressed by poly-ribosylation of HnRNP
attached to E-cadherin 5’UTR. Human CDH1 pro-protein harbors topological domains: signal peptide (S), pro-peptide (PRO), extracellular with cadherin repeats
EC1-EC5 domains, transmembrane (TM, with proximal CH2 and distal CH3), cytoplasmic domain (CD); binding sites of delta1-catenin and presenilin-1 (PS1),
p120-ctn, β-catenin (βCTN), calcium; ubiquitination and short intracellular half-life sites rich in proline (P), glutamic acid (E), serine (S) and threonine (T) (PEST);
motif highly conserved (Leu-Ser-Ser-Leu); acidic residues cluster of endocytic signal (DEE 602–604). Cleavage sites by proteases (scissors): metalloprotease
(MMP), gamma-secretase/PS1 (presenilin-1) and caspase 3. Inhibitory or stimulatory phosphorylation sites for casein kinase-1 (CK1) (red) and CK2, GSK3β and
PDK1 respectively. N-glycosylation at Asn-483 is essential for expression, folding and trafficking. Ligth blue horizontal lines indicate protein binding domains
the E-cadherin proprotein contains a furin-cleavable motif
[SSPGLRRQKR] (Fig. 1) [73, 136], and sequence
specificity for other mammalian convertases . In contrast,
mature E-cadherins are inactivated by cleavage in the EC
domain mediated by matrix metalloproteinases  and
others proteases [89, 153], in a process known as
ectodomain shedding, thus promoting the invasion [44, 122, 187]
In addition, it has also been reported that E-cadherins
can adhere heterophilically to integrins αEβ7 and α2β1
[30, 176, 205], killer-cell lectin-like receptors G1 ,
and numerous infectious agent proteins that target
Ecadherins as an entry receptor [5, 36, 132].
E-cadherin function control via CD
In active functionally adhesion complexes E-cadherin
associates with intracellular components forming AJs.
Ecadherin CD interacts with several cytoplasmic proteins,
being the catenins the best understood: β-catenin or
γcatenin, α-catenin, and p120-catenin (p120-ctn) [41, 128,
133, 134, 165]. A homolog of β-catenin,
γ-catenin/plakoglobin , can substitute it under some circumstances
. When they are fully incorporated in complexes
with cadherins, these three catenins associate with a
stoichiometry of one of each catenin per cadherin
molecule [90, 147]. β-catenin binds directly to the distal ~72
amino acids of the E-cadherin CD through a 30-amino
acid “core”, anchoring indirectly to α-catenin (Fig. 1)
. P120-ctn binds independently to the ~29 amino
acid membrane-proximal region of the cadherin CD
[165, 199] (Fig. 1). α-Catenin associates with the actin
cytoskeleton [167, 214] and numerous adaptor proteins
to strengthen cell-cell adhesion [1, 199].
Several cleavage fragments of E-cadherin CD and
disassembling of their adhesive complexes have been
reported. During apoptosis or calcium influx, presenilin 1
(PS1)/γ-secretase cleaves between human E-cadherin
residues Leu731 and Arg732  and caspase-3 cleaves
on site 747-DTRD-750 and releases a 25-kDa fragment
[93, 183]. In addition, during tumoral progression
calpain mediates E-cadherin proteolysis  (Fig. 1).
It has been proposed that while β-catenin and plakoglobin
facilitate indirect interactions between classic cadherins and
the actin cytoskeleton at AJs in vivo, p120-ctn subfamily
members induce the lateral (cis) clustering of cadherins
, and the tethering of signaling or regulatory entities,
such as kinases and phosphatases . P120-ctn also
stabilizes cadherins at the cell membrane by modulating
cadherin membrane trafficking (endocytosis-recycling) and
degradation [21, 139, 211]. Catenins are modified by kinases
and/or phosphatases that are enriched at cell-cell contacts
[6, 42, 52, 118, 203]. E-cadherins, in turn, are normally
maintained in a tyrosine-dephosphorylated state through
the action of phosphatases that are crucial for stabilizing AJs
[51, 135]. In some cell contexts, phosphatase inhibition
promotes release of E-cadherins and β-catenins from cell-cell
contacts, enabling cytoplasmic catenins to relocate and
function in the nucleus and promoting E-cadherin
proteolysis . Like phosphatase inhibition, receptor tyrosine
kinase stimulation disassembles cell contacts mediated by
cadherin─β-catenin─α-catenin [18, 203]. In addition,
p120-ctn is an important modulator of RhoGTPase
activities, such as RhoA, Rac1 and Cdc42 [3, 4, 142] and gene
transcription [43, 95, 149, 162, 180]. On the other hand,
p120-ctn interacts with tubulin influencing microtubule
stability and dynamics, and thereby affects cell motility and
directional migration independently of the cadherin adhesion
system [81, 170] (Fig. 2).
As for α-catenin, it modulates the actin-cytoskeleton
organization because it can occur either in a monomeric
or a homodimeric form [13, 50, 65]. Upon the application
of force on epithelia, the conformational change of
monomeric αE-catenin uncovers the vinculin binding site,
allowing vinculin to bind, and recruit additional F-actin to
the cadherin-catenin complexes [126, 214]. Additionally,
ZO-1, spectrin, vinculin  and Eplin  assemble
Fig. 2 (See legend on next page.)
(See figure on previous page.)
Fig. 2 Signaling pathways involved in cell-cell adhesion mediated by E-cadherin in physiological and pathological conditions. a Shortly after their
synthesis, cadherins associate with β-catenin and phosphorylation on the RER avoid degradation of uncomplexed cadherins and the pro-region
cleavage by furin proteases in the trans-Golgi network. When the cis E-cadherin surface pool increases, pro-domain cleavage induces dimerization,
trans homophilic bonding and E-cadherin adhesive activity. Delivery of newly synthesized E-cadherin to the basolateral cell surface should be
mediated by Rab 11, golgin-97, Sec5, 6, Protein Associated with Lin Seven 1 (PALS), aquaporin 3 (AQP3), p120-ctn, and possibly β-catenin, via
localization at the centrosome. b AJs-disassembly by dysfunction of E-cadherin─catenin complexes (CCC) releases catenins that accumulate in
the cytoplasm. β-catenins are then sequestered and phosphorylated by the adenomatous polyposis coli (APC)–axin–glycogen synthase kinase 3β
(GSK-3β) complex, inducing their ubiquitination by the E3 ubiquitin-ligase βTrCP subunit for proteosomal degradation. However, if at the same
time the Wnt signaling pathway is activated, GSK-3β is repressed and β-catenins are no longer phosphorylated and are translocated to the nucleus
where their bind TCF/LEF1 transcription factors and modulate gene expression involved in cell proliferation and migration. Cytoplasmic p120-ctns
detached from AJs, in turn, activate Rac1 and Cdc42 through Vav2 (Rho-GEF) and represse Rho, promoting filopodia and lamellipodia projections. PI3K
is recruited to the membrane by intact E-cadherin adhesion junctions, where it generates PIP3. This activates Tiam1 (Rho-GEF) and subsequently Rac1
and Cdc42, sequestring the GTPase-activating protein (IQGAP1), avoiding IQGAP-binding to β-catenins, and displacing α-catenins from the CCCs, thereby
disrupting the CCC-anchoring to the cytoskeleton. Thus, while the activation of Cdc42 and Rac1 induces the formation of filopodia and lamellipodia
respectively, Rho induces the formation of actin stress fibers. Cytoplasmic p120-ctn also can translocate to the nucleus to associate with Kaiso and modulate
actin to E-cadherin-catenin complexes. In parallel, the
non-junctional cytosolic homodimeric αE-catenin pool
inhibits the Arp2/3 complex, reducing membrane dynamics
by preventing F-actin branch-formation .
Dynamics of E-cadherin-mediated cell-cell adhesion
Establishment of adherens junctions
Epithelial AJs are built on a foundation of homophilic
contacts between (E or P)-cadherin clusters on the surface
of adjacent epithelial cells [62, 117]. Cadherins alone are
not sufficient for AJ formation; rather, cooperation
between nectins and cadherins is required [166, 188] (Fig. 3).
Appearently, the trans-interacting nectin inhibits
nontrans-interacting E-cadherin endocytosis through afadin,
Rap1, and p120-ctn, thereby further non-trans-interacting
E-cadherin accumulates in the nectin-based cell-cell
adhesion sites for AJ formation . Once AJs have been
established through intracellular partner binding to the
cytoskeleton, E-cadherin contacts modulate actin filament
organization at the underlying cortex [10, 50, 155] and
microtubules network [130, 131].
It is known that catenins, including β-catenins, α-catenins,
and p120-catenins, bind to immature E-cadherins while
traveling through the endoplasmic reticulum and Golgi
apparatus [40, 71]. Following synthesis in the rough
endoplasmic reticulum and phosphorylation of the cytoplasmic
domain, the E-cadherin pro-region is cleaved by furin
proteases in the trans-Golgi network, an event that is
mandatory for the mature cadherin to function in adhesion
[59, 75, 116] (Fig. 2). Via golgin-97 dependent
tubulovesicular carriers, E-cadherins leave the Golgi complex , and
subsequently fuse with an intermediate recycling endosome,
in route to the basolateral plasma membrane. This pathway
for E-cadherins trafficking is tightly integrated with other
proteins involved in epithelial polarity, such as Sec5, 6, and
15 [107, 193], Rab 11 , PALS (Protein Associated with
Lin Seven 1), and aquaporin 3 (AQP3) , and it
determines lumen formation  (Fig. 2).
The function and regulation of E-cadherins
posttranslational modifications in vivo have remained poorly
defined. While the phosphorylations to eight serine residue
cluster within a region that binds β-catenin modulate the
βcatenin affinity and strengthen cell–cell adhesion , the
E-cadherin cytoplasmic O-glycosylation (O-GlcNAc) blocks
its cell surface transport, reducing intercellular adhesion
. In addition, E-cadherins have four consensus sites
Asn-X-Ser/Thr for N-glycosylation in EC4 and EC5
domains , most of them conserved among species (Fig. 1).
It has been established that, while the N-glycans at Asn 633/
483 are essential for E-cadherin folding, trafficking, and
proper expression , their modification with complex
Nglycans weakens AJs [121, 157] (Fig. 2).
Signaling and maintainance of adherens cell-cell junctions
Chemical [3, 85, 86, 149] and mechanical [110, 214]
signals from cell-cell junctions can be transduced through
E-cadherin-CD via β-, α- and p120-catenin to the
cytoplasm or nucleus. Mechanical stimulation generated by
tumor cell proliferation leads to β-catenin
phosphorylation via Src kinase at the site of its interaction with
Ecadherin, increasing β-catenin nuclear localization, and
upregulating the oncogenes Myc and Twist1 . In
physiological state, the formation of junctional
complexes triggers activation of the
phosphatidylinositol-3kinase (PI3K)–Akt–protein kinase B pathway 
because the PI3K-p85 subunit associates with AJs through
direct binding to β-catenin  (Fig. 3). After
recruitment of PI3K, phosphatidylinositol-(3,4,5)-triphosphate
(PIP3) is generated, and guanine nucleotide exchange
factors, that contain PIP3-binding pleckstrin homology
domains, are recruited to the membrane and activate
Rac1 [105, 210] or Cdc42 . This stimulates
membrane actin dynamics adjacent to the initial contact site,
increasing the probability of additional E-cadherin
engagements. α-Catenins, in turn, homodimerizes and are
released from the cadherin─catenin complexes to bind
Fig. 3 Dynamics of E-cadherin-mediated cell-cell adhesion Epithelial AJs are constructed on a foundation of homophilic contacts between
Ecadherin clusters. Previous contacts between nectins inhibit non-trans-interacting E-cadherin endocytosis through afadin, Rap1, and p120-ctn, and
increase their concentration at cell-cell adhesion sites. Immediately after E-cadherin trans-interaction, the junction complexes trigger activation of
the phosphatidylinositol-3-kinase (PI3K)–Akt–protein kinase B pathway. Phosphatidylinositol-(3,4,5)-triphosphate (PIP3) is generated, and guanine
nucleotide exchange factors are recruited to the membrane, activating Rac1 or Cdc42 and reducing Rho activation, which stimulates membrane and
actin dynamics adjacent to the initial site of contact, increasing the probability of additional E-cadherin engagements. Alpha-catenin homodimerizes
and is released from the cadherin-catenin complexes to bind at and antagonize with Arp2/3, facilitating the belt formation of unbranched actin
filaments. While vinculin, afadin and alpha-actinin link with actin cytoskeleton, β-catenin and p120-ctn also link with tubulin cytoskeleton to route both
vesicles of newly synthesized E-cadherin-catenin and E-cadherin-recycling-endosomes to the cell-cell contact sites. Down-stream of Rac and Cdc42,
IQGAP1 binds β-catenin, which could localize in membrane ruffles and control cadherin internalization via SNX-1 preventing E-cadherin lysosomal
degradation and recycling of E-cadherin back to the cell surface for AJ maintenance. P120-ctn binding covers cadherin juxtamembrane domain inhibiting
RhoA locally and adaptor complex-binding that recruits cadherins into a coated pit. Thus, E-cadherin becomes withheld in plasma membrane junction
domains. Meanwhile, PtdIns(3,4,5)P3 accumulation in the membrane signals for the formation and expansion of the baso-lateral surface, while Rac1 promotes
cell polarity and lumen formation, cell cycle arrest of confluent epithelial cells, and survival of polarized epithelial cells. In parallel, E-cadherin downregulates
ligand-dependent receptor tyrosine kinase activation, such as EGFR stabilizing cell-cell contacts. Insert: traffic of E-cadherin vesicles via p120-ctn or β-catenin
coupled to kinesin for delivering to newly forming or remodeling junctions
at actin and antagonize Arp2/3 function, inhibiting actin
branching and facilitating belt formation of unbranched
actin filaments. Simultaneously, other actin-binding
proteins such as vinculin, afadin and α-actinin link with
actin cytoskeleton, and β-catenin and p120-ctn link with
tubulin cytoskeleton to route vesicles of
Ecadherin─catenin to the cell-cell contact sites.
Meanwhile, PtdIns(3,4,5)P3 accumulation in the membrane
signals for the formation and expansion of the
basolateral surface, whereas Rac1 promotes polarity orientation
and lumen formation. In tissue and cell-type specific
contexts, Rac1 also triggers the activation of downstream
signaling effectors, promoting cell cycle arrest of
confluent epithelial cells, and survival of polarized epithelial
cells . Therefore, cadherins function in tissue
morphogenesis by controlling both cell-cell adhesion and
cell signaling. In this way, cadherins are involved in
determining cell shape, position, migration [33, 68, 92, 125,
186], polarity [16, 200] and proliferation [96, 172], as
well as tissular folding [201, 202]. In adherens junctions,
E-cadherins and catenins determine cell-cell contact
survival and epithelia function .
AJs are very dynamic structures that undergo constant
remodeling. This can be low-scale remodelling involving
replacement of individual or groups of molecules within
the adhesive clusters without disrupting steady-state
intercellular adhesions. It can also be large-scale
junctional rearrangements that accompany breakdown and
reformation of cell-cell contacts .
Growth factors (GFs) as specific regulators
of E-cadherin─catenin traffic
GFs are responsible for crosstalk between cell proliferation,
migration, and adhesion. GFs bind to their specific receptor,
cause cell-cell dissociation coupled to E-cadherin
endocytosis and recycling back to the cell surface by several
mechanisms [22, 23, 148] (Fig. 3). Co-regulation of cadherins and
GF signaling is prominent in epithelial to mesenchymal
transitions (EMT) and tumorigenesis [20, 88]. E-cadherins,
in turn, modulate signal transduction by interacting with
receptor tyrosine kinases, including the epidermal growth
factor receptor (EGFR) [29, 163]. Among them, thyroid
hormones (THs) modulate energy metabolism, having a
great influence on growth and development by independent
mechanisms . An increasing number of studies show
the THs action in different parallel signaling pathways via
membrane receptors, cytoplasmic partners and thyroid
hormone receptors (TRs) [72, 106]. TRs heterodimerize with
retinoid X receptors (RXRs) and bind to T3 response
elements (TRE) located within the genomic regions of target
genes . In the absence of T3, TRs interact with
corepressor proteins to inhibit TH-regulated target gene
transcription (Fig. 4). Following T3 binding, co-repressors are
displaced and co-activator proteins are recruited to the
ligand-bound TR complex, so as to facilitate T3-dependent
activation of the target genes. Complexity increases because
the diploid organisms have THRA and THRB genes that
encode the TRα and TRβ isoforms respectively, which are
ubiquitously expressed [109, 175, 212, 213]. Moreover,
depending on species, tissue or experimental systems, there
are predominant TR cell isoforms, and each gene can
generate different proteins using different promoters and/or
alternative splicing [109, 175, 213]. In addition to functions
mediated by TRs, THs also exert rapid non-genomic actions
that are initiated at the cell membrane. For example, the
αvβ3-integrin binds to THs, activating the
mitogenactivated protein kinase (MAPK) cascade [45, 119] for
modulating the membrane ion channels, Na+/K+ exchanger
and Ca2+ATPase, as well as the actin cytoskeletal
components  (Fig. 4).
Among genomic mechanisms, it is known that
transcriptional repression of E-cadherins is mediated either
by promoter CpG hypermethylation  or activation of
repressors binded at E-boxes or brain-specific silencers,
such as Snail and Slug , Twist  and E12/E47
(E2A gene product) . In contrast, the miR-200
family directly targets repressors ZEB1 and ZEB2,
promoting E-cadherin expression upregulation [103, 104]
(Fig. 1). In hormonal signaling routes, it is known that
the activated androgen receptor binds to promoter and
also represses E-cadherin gene expression, promoting
metastasis by EMT .
Conversely, our results suggest that T3-TRs promote
E-cadherin, β- and α-catenin gene expression in vivo
and EMT inhibition [56, 85]. E-cadherin locus
upregulation can be mediated by an enhancer element at
intron 1 [12, 25, 69, 70]. In addition, Stemler Stemmler
et al.  reveal a complex mechanism of gene
regulation at mouse E-cadherin locus intron 2. While in
differentiated epithelia intron 2 sequences are required both
to initiate transcriptional activation and additionally to
maintain E-cadherin expression during embryogenesis,
the level of intron 2-dependent E-cadherin expression is
relative to the tissues and developmental timing. Thus,
early embryogenesis requires intron 2 for the onset of
expression, but at later stages, a second mechanism
initiates E-cadherin expression independently of intron 2,
although for high-level expression the support of the
intron 2 enhancer elements is still required. The onset
of the second wave of expression was detected in the
surface ectoderm differentiate to form skin, and in the
gut endoderm (around E12.5). A locus control region
(LCR), in turn, might influence gene activity for proper
activation and downregulation, sited upstream of
cadherin clusters [184, 185] with a vital role for the large
intron 2 (Fig. 1). Striking, cadherin superfamily genes
display a higher average total intron number and
significantly longer introns than other genes and across the
Fig. 4 T3-actions from genomic and non-genomic effects on cell adhesion and differentiation during vertebrate development. THs modulate energy
metabolism, growth and development by independent mechanisms. While thyroid calorigenesis is influenced predominantly via nuclear receptors,
many of the TH effects over development are thought to be mediated via cytosolic and membrane partners. E-cadherin trans-interaction triggers
activation of the phosphatidylinositol-3-kinase (PI3K)–Akt–protein kinase B pathway bound to β-catenin, generating phosphatidylinositol-(3,4,5)-triphosphate
(PIP3), recruitment of guanine nucleotide exchange factors, activation of Rac1 or Cdc42 and Akt, and reduction of Rho activation. In addition, TRα or TRβ forms
a cytoplasmic complex with the p85 subunit of PI3K, inducing protein kinaseB/Akt nuclear translocation and inhibition of the Wnt/β-catenin pathway through
its interaction and consequent sequestration of β-catenin. The process results in down-regulation of cell proliferation. Simultaneously, TH binding to TRs
causes heterodimerization with retinoid X receptors (RXRs), binding to T3 response elements located within the genomic regions and shooting target gene
transcription. In the absence of T3, TRs interact with co-repressor proteins to inhibit target gene transcription. Following T3 binding, co-repressors are displaced
and co-activator proteins are recruited to the ligand-bound TR complex, facilitating T3-dependent activation of the target genes. Besides the TR-mediated
functions, THs also exert rapid non-genomic actions that are initiated at the cell membrane. Integrin αvβ3 is a specific membrane receptor for THs, which
mediate activation of the mitogen-activated protein kinase (MAPK) intracellular cascade. TH-dependent MAPK activation subsequently results in modulation
of the membrane potential by regulation of ion channels, activation of the Na+/K+ exchanger and Ca2+ATPase, or regulation of actin cytoskeletal components
anchored at the cell membrane. TH-activated MAPK, in turn, can rapidly translocate to the nucleus inducing serine phosphorylation of TRs, thereby resulting
in the induction of angiogenesis or tumor cell proliferation. Nuclear targets for phosphorylated TRs include the transcription factors p53, STAT1a and STAT3
entire vertebrate lineage . Particularly, the human
genome has an uncommon high frequency of MIR and
MaLR regulatory-associated repetitive elements at
5’-located introns, concomitant with increased de novo
intronic transcription. Therefore, these intronic-specific
sites may constitute targets of cadherin superfamily
expression regulation, both in homeostasis and illness.
Thus, searching for some of those physiological needs
to sustain epithelial life, we have analyzed cell adhesion
molecule response to 3,5,3’-triiodothyronine (T3),
detecting morphometric evidences of gene upregulation exerted
by T3 on E-cadherin, β- and α-catenin expression in
different epithelial cell types of the metamorphosing anuran
foregut . Coincidentally, mouse β-catenin gene
upregulation and transrepression by TH-TR [61, 158], as well as
the impact of TH signaling in development, homeostasis
and cancer susceptibility of mouse intestine  have
been reported. T3-TRα1 binds directly to β-catenin
geneintron 1 specific TRE in the intestine, increasing its
expression in an epithelial cell-autonomous way 
(Fig. 5). This is parallel to positive regulation of
proliferation-controlling genes, such as type D cyclins and
c-myc, which are known targets of the Wnt/β-catenin
pathway , synergizing Wnt pathway and inducing
crypt cell proliferation and promoting tumorigenesis
. In contrast, CTNNB1 transrepression is mediated
by binding of the TRβ-RXR complexes on TREs located in
the human promoter between −807 and −772 (Fig. 5) .
Therefore, liganded TRβ acts as a tumor suppressor via
inhibition of the expression of a potent tumor promoter,
the CTNNB1 gene.
Even though TH signaling controls the proliferation of
the intestinal epithelial progenitors in both amphibians
and mammals, it has been suggested that TH control on
the Wnt/β-catenin pathway does not appear to play a
central role in amphibians [24, 178]. However, our in
vivo experiments contradict this hypothesis, since we
have detected early upregulation (24 hs) of E-cadherin,
β- and α-catenin genes in the Xenopus laevis gut .
During metamorphic climax, larval cell apoptosis
coexists with pre-adult (juvenile) cell proliferation and
differentiation, and with cell-cell junction
assembly─disassembly, that require a complex signal network to
control tissular homeostasis. We found that T3 modulates
epithelial adhesive potential during gut remodeling in X.
laevis development, early and directly activating
Ecadherin, β-catenin and α-catenin genes, and
downstream, modulating small GTPases and other proteins
involved in adhesive epithelial properties. Using
INSECT2.0 web server to predict the occurrence of
CisRegulatory Modules (CRMs) , we found putative
TERs in X. laevis E-cadherin, β-catenin and α-catenin
genes, but not in the p120-ctn gene . Among
evaluated small GTPases, gastrointestinal Rac1-mRNA levels
significantly increased at 24 hs T3-treatment correlated
with heightened “lamellipodia” or membrane
protrusions. In contrast, at 5 days post T3-treatment
RhoAmRNA levels decrease while the important Rap1-mRNA
increasing suggests that membrane Rap1-dependent
Ecadherin recycling occurs at metamorphic climax end.
Cdc42 and Arp2 actin nucleation protein became
constant both during T3-induced and natural
THs exert profound effects on tissues. Among them,
cell-type dependent proliferation and differentiation
both in mammalian skin [101, 113, 164, 195] and gut
[158, 178], as in anuran kidney , skin  and gut
[55, 56, 85]. These effects are regulated by
phosphorilation levels of several partner proteins  and
modulation of gen expression [56, 85]. Among the non-genomic
effects of thyroid hormones, it appears that T3 activates
PKA to in turn induce β-catenin nuclear translocation
by phosphorylation at Ser675 site, thereby β-catenin
modulates cyclin-D1 gene transcription and induces cell
proliferation (Fig. 5) . In contrast, TH causes
astrocyte differentiation through both initial PKA activity and
later by phospho-MAP kinase (p-MAPK or p-ERK) .
Postbirth, Schwann cell E-cadherin expression is highly
regulated through cAMP-PKA activation for maintaining
structural integrity . Thus, E-cadherin can negatively
regulate, in an adhesion dependent manner, the
liganddependent activation of divergent classes of RTKs, by
inhibiting their ligand-dependent activation in
association with a decrease in receptor mobility and in
ligandbinding affinity  (Fig. 5).
Therefore, the function of THs and their TRs in cell
proliferation, differentiation and apoptosis is not
homogenous, because it depends strongly on the
physiopathological context; that is, the cell-type, ontogeny
(progenitor or differentiated cell) and health (normal or
tumoral cell). Although TH-dependent processes are highly
coordinated, in turn, the local requirements cannot be
governed by global mechanisms, such as an alteration of
the thyroid gland function and variations in plasma TH
concentrations. Instead, they require tissue-specific
regulation mediated by deiodinases. Thus, in mammals, T3
induces type 2 deiodinase (D2) and E-cadherin expression,
which sequesters β-catenin and reduces both β-catenin/
TCF complex and type 3 deiodinase (D3) activation levels.
Consequently, the local active T3-level increases and
promotes cell differentiation and reduces its oncogenic effects
in intestinal cells (Fig. 5) . Recently, this hypothesis
has been again supported by Catalano and coworkers ,
who have found that increased intracellular TH
concentration through D3 depletion induces cell differentiation
and sharply mitigates tumor formation.
In this context, it is possible to postulate that during
organ remodeling T3 induces epithelial stem cell
Fig. 5 T3-control model of E-cadherin─β-catenin complex on gastrointestinal epithelial cells. THs and RTs function in cell proliferation, differentiation and
apoptosis is not homogenous, because it depends strongly on physio-pathological context; that is, the cell-type, ontogeny (progenitor or differentiated cell)
and health (normal or tumoral cell). However, it is possible to postulate that, while T3 induces epithelial basal cell proliferation via EGF-EGFR and cAMP-PKA
signaling, T3 activates transcription of E-cadherin, β- and α-catenin genes in epithelial cells programmed to differentiate on pre-adult gut epithelia cells and
inhibiting their EGF-EGFR dependent proliferative signal, as well as inhibiting their TH-integrin αvβ3 dependent migratory signals. In addition, because
Ecadherin increases β-catenin sequestration at the plasma membrane, it then promotes cell differentiation by diminishing the β-catenin/TCF complex pool. At
the same time, TSH-TSHR (receptor) signaling via cAMP stabilizes the assembly and retention of E-cadherin at the cell surface. TRα1 binds to β-catenin
geneintron 1-TRE (TRE-int1) in the intestine, increasing its expression via TH-binding. In parallel, TRα1 positively regulates the proliferation-controlling genes such as
type D cyclins and c-myc, which are known targets of the Wnt/β-catenin. Increase of β-catenin/Tcf4, in turn, reduces the TRα1 transcriptional activity on its
target genes. On the other hand, CTNNB1 transrepression is mediated by binding of the TRβ-RXR complexes to promoter TREs
proliferation via EGF-EGFR and cAMP-PKA signaling,
and in parallel, T3 leads to repression of this via in a
subgroup of these stem cells, and simultaneously
increases E-cadherin, β- and α-catenin transcription
via TH-RT to differentiate them to pre-adult
(juvenile) gut epithelia cells (Fig. 5). In addition, the
erichment of junctional E-cadherins sequestrates
βcatenins, reducing their β-catenin nuclear
translocalization and D3 disponibility, thereby strengthening
Unquestionably, E-cadherin is deeply involved in
establishing cell polarity and differentiation, and thereby in the
establishment and maintenance of tissue homeostasis during the
development and the entire life of pluricellular organisms,
mainly metazoans. Therefore, this transmembrane receptor
is a potent suppressor of tumoral invasion and metastasis.
Thus, E-cadherin must continuously react both at
extraand intracellular signals, some of which are classical, and
very well known.
This review summarizes findings supporting the
central role of thyroid hormones in controlling the
availability and functionality of E-cadherin, through membrane,
cytoplasmic and gene expression activities that regulate
cell proliferation, differentiation, migration, and thereby
AJ: Adherens junctions; AQP3: Aquaporin 3; CD: Cytoplasmic domain; D2: Type
2 deiodinase; D3: Type 3 deiodinase; EC: Extracellular domain; EGFR: Epidermal
growth factor receptor; EMT: Epithelial to mesenchymal transitions; GF: Growth
factor; HAV: Histidine-alanine-valine; MAPK: Mitogen-activated protein kinase;
O-GlcNAc: O-glycosylation; p120-ctn: p120-catenin; PALS: Protein Associated
with Lin Seven 1; PI3K: Phosphatidylinositol-3-kinase; PIP3:
Phosphatidylinositol(3,4,5)-triphosphate; PS1: Presenilin 1; RT: Thyroid hormone receptor;
RTK: Membrane-receptor tyrosine kinase; RXR: Retinoid X receptor; T3:
3,5,3’triiodothyronine; TH: Thyroid hormone; TM: Trans-membrane domain; TRE: T3
We are grateful to Professor Diana Mónica Waigandt for her help with the
revision of the English version of the manuscript for publication and to Dr.
Alejandro Peralta Soler for his critical reading and valuable suggestions to
improve the manuscript.
This work was supported by grants from: National Agency for Scientific and
Technological Promotion-MINCYT, Argentina and UNER: PICTO-2009-209 (to
Victor Hugo Casco). SCYTFRH-UNER 6019–1 (to Victor Hugo Casco);
SCYTFRHUNER 6067–1 (to Victor Hugo Casco); SCYTFRH-UNER 6088–1 (to María
Ethical approval and consent to participate
The research protocol was approved by the local Research Institutional Ethics
Committee of Entre Ríos National University.
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