REVIEWS

Adhesion molecule signalling:

not always a sticky business
Ugo Cavallaro*|| and Elisabetta Dejana‡§
Abstract | The signalling activity of cell adhesion molecules (CAMs) such as cadherins,
immunoglobulin-like CAMs or integrins has long been considered to be a direct consequence
of their adhesive properties. However, there are physiological and pathological processes that
reduce or even abrogate the adhesive properties of CAMs, such as cleavage, conformational
changes, mutations and shedding. In some cases these ‘adhesion deficient’ CAMs still retain
signalling properties through their cytoplasmic domains and/or their mutated or truncated
extracellular domains. The ability of CAMs to activate signal transduction cascades in the
absence of cell adhesion significantly extends their range of biological activities.

Adherens junction Adhesion between cells of the same type, which involves Claudins are the major adhesive proteins at tight
Protein complex that forms the binding of cell adhesion molecules (CAMs) on junctions; however, a direct signalling activity of these
at the boundaries between adjacent cells, regulates fundamental processes such proteins has yet to be reported, although several signal-
epithelial or endothelial cells
as cell differentiation, contact inhibition of cell growth ling proteins have been found to co-distribute at tight
and promotes and stabilizes
cell–cell adhesion.
and apoptosis. These processes ensure correct tissue junctions (reviewed in REF. 7). Tight junctions mostly
organization in development, and tissue regenera- act to control paracellular permeability in epithelial
Tight junction tion in the adult. Homophilic inter actions between and endothelial cells, and to establish a boundary that
Protein complex (usually apical identical CAMs mediate mechanical adhesion among restricts lipid and protein diffusion between the apical
to adherens junctions) that
‘seal’ the cell–cell contacts,
cells but also, importantly, CAMs are able to propa- and basolateral membrane domains of these cells, thus
thus preventing the diffusion gate intracellular signals. This last function is due to establishing cell polarity. These functions appear to
of substances across epithelial their connections with the major signalling networks be dependent on the adhesive properties of claudins,
or endothelial barriers. that control most cellular responses. Therefore, these and it is still unclear whether and how these proteins
adhesive proteins not only maintain tissue integrity may propagate intracellular signals (for reviews, see
but also may serve as biosensors that modulate REFS 7,8). Therefore, claudins will not be discussed in
cell behaviour in response to the surroundin g this Review.
*Cell Adhesion and Signalling microenvironment. Ig-CAMs are cell-surface glycoproteins that express a
and ‡Angiogenesis and
Cell–cell adhesion is mostly mediated by cadherins variable number of immunoglobulin-like loops in their
Vascular Biology,
FIRC Institute of Molecular at adherens junctions , claudins at tight junctions and extracellular domain. Most Ig-CAMs have a transmem-
Oncology (IFOM), immunoglobulin-like CAMs (Ig-CAMs) along the brane domain but some are linked to the cell surface by a
Via Adamello 16, intercellular boundary, although some adhesion mole- glycophosphatidyl inositol anchor. As is the case for cad-
20139 Milan, Italy. cules, such as nectins, are localized both at adherens herins, homophilic interactions between Ig-CAMs con-
§
Department of Biomolecular
Sciences and Biotechnologies,
junctions and at tight junctions (reviewed in REFS 1–6). tribute to cell–cell adhesion, although for Ig-CAMs the
School of Sciences, University Cadherins engage in Ca2+-dependent homophilic trans- binding is Ca2+-independent. The cytoplasmic tail of
of Milan, Via Celoria 26, interactions in which a cadherin molecule on one cell Ig-CAMs also interacts with cytoskeletal proteins such
20133 Milan, Italy. binds to an identical cadherin molecule on an adjacent as actin, ankyrins and spectrin9.
||
Present address:
cell (FIG. 1a). After binding, cadherins cluster laterally in The ability of CAMs of the cadherin and Ig-CAM
Molecular Medicine Program,
IFOM–IEO Campus, cis at cell–cell junctions and form a zipper-like structure superfamilies to modulate cellular responses has been
European Institute of along the cell periphery that promotes tight adhesion traditionally viewed as a consequence of their adhe-
Oncology, Via Ripamonti 435, between cells. Cadherins are linked to a large variety sive functions. However, the possibility that CAMs also
20141 Milan, Italy. of intracellular partners that mediate intracellular mediate adhesion-independent signalling is supported
e-mails: [Link]@ifom-
[Link]; elisabetta.
signalling and modulate the organization of the actin by several reports in the literature that suggest that they
dejana@[Link] cytoskeleton to provide the dynamic forces necessary may do so in different ways, such as by interacting with
doi:10.1038/nrm3068 for correct tissue morphogenesis. growth factor receptors, transcription cofactors and

nATuRe RevIews | Molecular cell Biology voluMe 12 | MARCH 2011 | 189

© 2011 Macmillan Publishers Limited. All rights reserved

REVIEWS

C %[VQRNCUO D overall, these findings support the view that CAMs are
)TQYVJ bona fide signalling receptors, even though they have
HCEVQTU atypical signalling properties. understanding the molec-
%CFJGTKP
)TQYVJ ular mechanisms of adhesion-dependent and adhesion-
HCEVQTTGEGRVQT independent CAM signalling may have clinically relevant
βECVGPKPQT implications. CAMs are frequently quantitatively and
RNCMQINQDKP
qualitatively altered in a broad range of diseases such as
αECVGPKP cancer, vasculopathies, epithelial and neurological dis-
+PVTCEGNNWNCT
UKIPCNNKPI
orders. CAMs may be cleaved or mutated in their extra-
R αECVGPKP RCTVPGTU cellular domain so that they lose their adhesive properties.
However, it is likely that the remaining intracellular tail or
#EVKP the soluble ectodomain that is shed — as well as mutated
4*1 6%(.'( extracellular domains — may still interact with signal-
R
-#+51 ling partners and promote direct or indirect intracellular
0WENGWU %[VQRNCUO signalling. How and when this occurs is still unclear, but
E F several examples of clearly proven adhesion-independent
(NQYUGPUQT signalling have been described.
EQORNGZ In this Review we discuss potential cases of signal-
ling through CAMs that do not necessarily require adhe-
//2U#&#/U %CURCUGU 2'%#/ sion. However, making this distinction is not always easy
γUGETGVCUG
because, for instance, the initiation of the signalling
8'ECFJGTKP process may involve cell–cell interactions and clustering
8')(4
of the adhesion molecules. Clustering per se may trigger
5JGCTUVTGUU intracellular signalling through the formation and activ-
(NQY
ity of multiprotein complexes consisting of, for example,
Figure 1 | Signalling through cadherins. Schematic view of the signalling pathways growth factor receptors, kinases or phosphatases10,11. The
0CVWTG4GXKGYU^/QNGEWNCT%GNN$KQNQI[
regulated by cadherins. a | Cadherins may signal indirectly by recruiting signalling purpose of this Review is not to present an exhaustive
proteins, including β-catenin, p120 catenin (p120) and junction plakoglobin catalogue of the signalling pathways triggered by differ-
(plakoglobin) to the membrane, which, once they are released from the cadherin tail, ent adhesion proteins. Instead, we discuss a few key
can translocate to the nucleus and regulate transcription. Unbound p120 can also examples of signalling by CAMs that do not necessarily
regulate cell motility by inhibiting the activity of RHO GTPases. When it is free in the require cell adhesion. It is possible that mutation or
cytosol, α-catenin can regulate actin bundling. The recruitment of α-catenin to the cleavage of the CAM protein domains that are important
cadherin complex is mediated by β-catenin. b | Cadherins may form signalling units by
for adhesion does not affect signalling or, conversely,
interacting with growth factor receptors such as vascular endothelial growth factor 2
(VEGFR2), epidermal growth factor receptor (EGFR), fibroblast growth factor receptor
that alterations in CAM-mediated signal transduction
(FGFR), platelet-derived growth factor receptor (PDGFR) and transforming growth may occur without altering adhesion. Although we focus
factor-β (TGFβ) receptors. Furthermore, they can form signalling units with intracellular on CAMs that mediate cell–cell adhesion, in particular
signalling partners such as kinases (for example, SRC family kinases and the Tyr-protein cadherins and Ig-CAMs, it should be emphasized that
kinase CSK (CSK)), as well as with phosphatases such as density-enhanced phosphatase adhesive proteins that are mainly involved in the inter-
(DEP1; also known as RPTPη), Tyr-protein phosphatase non-receptor type 11 (also known action of cells with matrix proteins, such as integrins,
as SHP2) and vascular endothelial protein Tyr phosphatase (VE-PTP; also known as also have adhesion-independent signalling properties,
RPTPβ). Finally, adaptor proteins such as SHC family members can also form signalling as reviewed elsewhere12,13.
units with cadherins. c | After MMP (matrix metalloprotease) or ADAM (a member of the
disintegrin and metalloprotease) family protease-mediated shedding of the ectodomain,
Adhesion-dependent functions of CAMs
intracellular proteases such as caspases and γ-secretase cleave the cadherin cytoplasmic
tail, which may then translocate to the nucleus and regulate transcription. d | Vascular
Adherens junctions are formed by the cadherin–
endothelial cadherin (VE-cadherin) in endothelial cells may form a flow sensor complex catenin complex (FIG. 1a). Cadherins are single-pass
with platelet endothelial cell adhesion molecule (PECAM) and VEGFR2. This complex transmembrane glycoproteins that form Ca2+-dependent
transfers intracellular signals that help the cells to adapt to conditions of shear stress. homophilic cis- and trans-interactions with their extra-
See the main text for more details. LEF, lymphoid enhancer factor; TCF, T cell factor. cellular regions and also link to catenins through their
cytoplasmic tails. At least 80 members of the cadherin
superfamily have been identified in mammals, includ-
other signalling proteins. In some cases CAMs signal ing desmogleins, desmocollins and protocadherins
indirectly by immobilizing their cytoplasmic partners at (for reviews, see REFS 14–17). Classical cadherins were
the membrane and preventing their diffusion in the cyto- originally named for the tissue in which they were
plasm and/or their nuclear translocation (reviewed in prominently expressed: for example, epithelial cad-
REFS 1–4,7). In other cases CAMs act as bona fide ligands herin (e-cadherin) in epithelial cells; neural cadherin
by binding to and activating growth factor receptors, as (n-cadherin) in the nervous system; and vascular
exemplified by the interplay between neural cell adhesion endothelial cadherin (ve-cadherin) in the endothelia.
molecule (nCAM) and fibroblast growth factor receptor Four major catenins have been found that coordinate
Intercellular boundary
(FGFR)10. signalling by CAMs may also be mediated by classic cadherin-mediated adherens junction dynamics
The narrow space between two their ability to recruit canonical signalling proteins at the and signalling: β-catenin, p120 catenin (p120), junction
tightly adjacent cells. membrane and promote their interaction and activation. plakoglobin (plakoglobin) and α-catenin.

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 REVIEWS

A major function of cadherins and adherens junc- C D %[VQUMGNGVCNTGOQFGNNKPI

tions is to promote homotypic cell–cell adhesion and, as PGWTKVGQWVITQYVJ
a consequence, to create and maintain tissue integrity.
This property is particularly important during develop- 2-%β++
)#2 5RGEVTKP
ment when single cells need to join to one another and
form a coherent tissue. In certain types of epithelia or
in the endothelium, adherens junctions are also indis- +I%#/ 0%#/
pensable for the correct control of permeability. For
instance, alterations in the expression of cadherins or
the organization of adherens junctions in the mucosae
or skin epithelium may generate pathological situations
5RGEVTKP %C/-++α
that include ulceration, infections and blisters (reviewed 4262α
in REFS 14–16). similarly, the inhibition of cadherin #EVKP
(#-
(;0
adhesive function in endothelial cells strongly increases
permeability to plasma proteins and circulating cells, 0GWTKVGQWVITQYVJ
PGWTQPCNUWTXKXCN
which leads to oedema and haemorrhages (reviewed
Figure 2 | adhesion-dependent signalling of ig-caMs.
in REFS 4,18). 0CVWTG4GXKGYU^/QNGEWNCT%GNN$KQNQI[
a | Homophilic trans-binding between immunoglobulin-
The adhesive properties of adherens junctions like cell adhesion molecules (Ig-CAMs) on adjacent cells
are also important for creating a boundary at the cell and lateral cis-interactions between Ig-CAMs on the
membrane that limits the free movement of membrane same cell generate zipper-like structures that stabilize
proteins and promotes the establishment of cell polar- cell–cell contacts. These adhesion complexes are further
ity 19,20. notably, adherens junctions frequently act in stabilized through their anchoring to the cytoskeleton
concert with tight junctions to control cell permeability by actin-binding proteins such as spectrin. b | Ig-CAM-
and cell polarity. Adherens junctions are required for mediated cell–cell adhesion leads to the recruitment and
correct assembly of tight junctions and, in the case of activation of signalling effectors, as shown here for neural
endothelial cells, cadherins may also transcriptionally cell adhesion molecule (NCAM)-mediated adhesion
and signalling. NCAM–NCAM interactions induce the
upregulate claudin expression11.
activation of calmodulin-dependent protein kinase IIα
Cadherin clustering at intercellular contacts usu- (CaMKIIα), which then activates receptor-type Tyr-protein
ally follows the formation of cell–cell contacts and is phosphatase-α (RPTPα) that, in turn, promotes the
important to strengthen cell–cell adhesion. However, activation of Tyr-protein kinase FYN (FYN), resulting in
clustering of cadherins may also increase signalling the stimulation of focal adhesion kinase (FAK) and in
activity, and it is hard to clearly separate these two neurite outgrowth and neuronal survival74. NCAM
aspects (see also below). homophilic interactions also stimulate the recruitment
Ig-CAMs are cell-surface glycoproteins that dis- of growth associated protein 43 (GAP43; also known as
play a variable number of immunoglobulin domains neuromodulin), resulting in the formation of a spectrin–
on their extracellular portion. They are normally dis- GAP43–protein kinase C βII (PKCβII) signalling complex
that promotes cytoskeletal remodelling and neurite
tributed along intercellular boundaries, without being
outgrowth75.
associated with specific adhesive structures such
as adherens junctions or tight junctions. Ig-CAMs
mediate Ca2+-independent cell–cell adhesion by means
of homophilic trans-interactions, with an Ig-CAM on FAK is recruited to the complex and is phosphorylated,
one cell binding to the same Ig-CAM type on an adja- thus inducing neurite outgrowth and neuronal survival
cent cell. The combination of these trans-interactions through the mitogen-activated protein kinase (MAPK)
at cell–cell contacts with cis-homophilic binding on the pathway. GAP43, however, promotes the formation of
same cell surface results in the assembly of zipper-like an nCAM–spectrin–GAP43–PKCβII complex, which
structures21 (FIG. 2a), similar to those described for cad- is also causally involved in neurite outgrowth22.
herins. These zipper-like structures are then stabilized Ig-CAMs can also establish heterophilic cis- and
by anchoring of the cytoplasmic tail of the Ig-CAMs to trans-interactions with other molecules, including dif-
components of the cytoskeleton, such as actin, ankyrins ferent members of the Ig-CAM superfamily, integrins,
and spectrin. As a result, Ig-CAM-mediated inter- cadherins, growth factor receptors and components
cellular contacts trigger various signalling cascades, of the extracellular matrix 23. Although this network of
as exemplified by the stimulation of the receptor-type interactions is known to specify the signalling proper-
Tyr-protein phosphatase-α (RPTPα)–Tyr-protein kinase ties of Ig-CAMs, in most cases the underlying molecular
FYn (FYn)–focal adhesion kinase (FAK) pathway and mechanisms remain elusive.
the spectrin–growth associated protein 43 (GAP43; Thus, various intracellular signals may be propa-
also known as neuromodulin)–protein kinase C (PKC) gated by cadherins and Ig-CAMs. In a few cases, CAMs
pathway, both of which are downstream of nCAM– may signal even in absence of cell–cell contact (that
nCAM interactions (FIG. 2b). various reports (reviewed is, within a single cell), although the establishment of
in REF. 22) support a model whereby neuronal RPTPα intercellular contacts may amplify the cell response.
mediates the constitutive interaction of nCAM with we focus on some typical examples in the remainder
FYn. upon nCAM homophilic binding and clustering, of this Review.

nATuRe RevIews | Molecular cell Biology voluMe 12 | MARCH 2011 | 191

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REVIEWS

C D E F 0%#/ as RPTPη)24. This process prevents clathrin-dependent

internalization of veGFR2 into endosomes and receptor
0ECFJGTKP
signalling from intracellular compartments. The major
()(4
()( effector of veGFR2 in intracellular compartments is
the MAPK pathway; thus MAPK-induced proliferation
2-%α 2-%β++ is inhibited as a result of this DeP1-mediated dephos-
phorylation of veGFR2 (REF. 25). Therefore, this effect of
4#5 2.%γ #-6 ve-cadherin contributes to cell growth inhibition.
2.%γ '4- 5*% 54%
%C/-++α //2 (45α The association of ve-cadherin with veGFR2 has
'4- '4- other important adhesion-independent implications.
on exposure to shear stress26, ve-cadherin can become
%GNNRTQNKHGTCVKQP %GNNOKITCVKQP
part of a mechanosensor complex 27 by acting as an adap-
0GWTKVG %GNNOQVKNKV[
QWVITQYVJ VWOQWTOGVCUVCUKU %GNNsOCVTKZCFJGUKQP tor between platelet endothelial cell adhesion molecule
(PeCAM) and veGFR2 (PeCAM directly transmits
Figure 3 | Modulation of FgFr signalling by NcaM and N-cadherin.
0CVWTG4GXKGYU^/QNGEWNCT%GNN$KQNQI[ mechanical force through sRC family kinase activa-
a | Cis-dimerization of neural cadherin (N-cadherin) promotes fibroblast growth factor
receptor (FGFR) activation in a ligand-independent manner. The downstream signalling
tion and veGFR2 activates phosphoinositide 3-kinase
cascade, involving phospholipase Cγ (PLCγ) and most likely calmodulin-dependent (PI3K)) (FIG. 1d). Formation of this complex leads to
protein kinase IIα (CaMKIIα), underlies N-cadherin-induced neurite outgrowth76. integrin activation, actin cytoskeleton rearrangement
b | The association with N-cadherin prevents FGFR internalization, allowing for and activation of the nuclear factor-κB (nF-κB) path-
sustained activation by FGF. This, in turn, promotes prolonged stimulation of the way. These effects of ve-cadherin are independent from
extracellular signal-regulated kinase (ERK) pathway and expression of matrix adhesion and clustering at junctions, and can also be
metalloprotease 9 (MMP9), inducing cell motility and conferring metastatic properties observed within single cells.
on cancer cells33,77. c | The signalling pathways induced by the canonical FGFR ligand,
FGF, are distinct from those activated by neural cell adhesion molecule (NCAM) (with FGFR: a promiscuous receptor in CAM signalling. FGFR
the exception of PLCγ and FGFR substrate 2α (FRS2α), which are activated by both
is a prototypical receptor Tyr kinase that upon binding
ligands), and include those pathways mediated by SHC family members, RAS family
members and protein kinase Cα (PKCα). Furthermore, FGF promotes the internalization
of its cognate ligand FGF undergoes dimerization and
and lysosomal degradation of FGFR, resulting in the rapid attenuation of signalling. autophosphorylation, thus triggering various signal
For further details, see REF. 10. d | The interaction of NCAM with FGFR triggers various transduction cascades28. The functional interaction
signalling pathways, including those mediated by PKCβII, AKT family members and of FGFR with CAMs was discovered in neural cells when
SRC family members, which ultimately leads to cell migration. Importantly, FGFR activity was implicated in the neurite outgrowth
NCAM-stimulated FGFR undergoes internalization and recycling to the cell surface, that is stimulated by n-cadherin, nCAM or the Ig-CAM
resulting in sustained signalling. For simplicity, only cis-interaction of NCAM with neural cell adhesion molecule l1 (l1)29. subsequently,
FGFR is depicted. However, studies with soluble NCAM support the notion that it has been proposed that n-cadherin facilitates FGFR
trans-interactions with FGFR also promote FGFR recycling and cell migration10. dimerization, thus initiating growth factor-independent
signalling 30. This effect is due to cis-dimerization of
n-cadherin, which is distinct from its adhesive activi-
CAM–growth factor receptor interactions ties31 (FIG. 3a). Downstream inhibitors of FGF signal-
several studies have implicated CAMs as modulators of ling have been shown to inhibit n-cadherin-mediated
growth factor receptor signalling. CAMs can directly or invasion32. In parallel with its capability to stimulate
indirectly bind growth factor receptors and control their FGF-independent signalling, n-cadherin is also involved
internalization and coupling to intracellular partners. in ligand-dependent FGFR activation. The extracellular
In general, cadherins exert their regulatory function domain of n-cadherin can interact with FGFR and
by affecting the interaction of the cognate ligand (the prevent receptor internalization, resulting in increased
growth factor) with its receptor and/or by modulating levels of the receptor at the cell surface and therefore
the biochemical response of the receptor itself to growth in sustained activation of FGFR by FGF33 (FIG. 3b). The
factor stimulation. This notion can also be extended to outcome of this crosstalk between n-cadherin and the
Ig-CAMs; however, Ig-CAMs can also, in some cases, FGF–FGFR system is the migration and invasion of
modulate receptor Tyr kinase (RTK) signalling in a single cells33, thus indicating that cell–cell adhesion is
ligand-independent fashion. The regulation of RTKs not required. nevertheless, whether intercellular con-
per se does not require the adhesive function of CAMs; tact affects n-cadherin-dependent regulation of FGFR
however, lateral clustering of CAMs may amplify activity remains elusive.
RTK-mediated signalling. In contrast with n-cadherin, nCAM exerts a nega-
tive regulation on FGF activity. Indeed, the interaction of
The VE‑cadherin–VEGFR2 partnership. ve-cadherin nCAM with FGFR is necessary and sufficient to repress
interacts with vascular endothelial growth factor recep- FGF-induced signalling, cell proliferation and matrix
tor 2 (veGFR2) and modulates its downstream signalling. adhesion34,35. Besides the regulation of FGF-mediated
The association of ve-cadherin with the veGFR2 com- activity, nCAM can also orchestrate FGFR signalling in
plex requires the cytoplasmic domain of ve-cadherin. a ligand-independent fashion10, providing a prototypical
when veGFR2 is bound to ve-cadherin, it is retained at example of how Ig-CAMs can regulate the duration of
the cell membrane, where it is quickly dephosphorylated RTK signalling, and the corresponding cellular response,
by density-enhanced phosphatase 1 (DeP1; also known by controlling the stability and intracellular trafficking of

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 REVIEWS

the receptor (FIG. 3). Following the pioneering studies of overall, it appears that CAM function may tran-
Doherty and walsh29, which implicated FGFR signal- scend adhesion by interacting with cell surface recep-
ling in nCAM-stimulated axonal growth, we showed tors and modulating their activity (FIG. 1b). In some
that nCAM regulates integrin-mediated cell–matrix conditions, CAM clustering adds to the complexity of
adhesion through a physical interaction with FGFR4 the situation by favouring cadherin interaction with
at the cell surface34. A number of reports10,36,37 have the receptors and/or by retaining the cadherin–growth
demonstrated that nCAM binds directly to FGFRs; factor receptor complex at the membrane (as is the case
thus, nCAM is emerging as a non-canonical ligand for for n-cadherin–FGFR1 or ve-cadherin–veGFR2 com-
this receptor family. As for many other growth factor plexes). These ways of signalling, although indirect, are
receptors, a key step in FGFR activation is its dimeriza- unique and different from the canonical view of signal-
tion upon ligand binding. The observation that nCAM ling through a soluble ligand binding to a membrane
cis-dimerizes on the cell surface38 suggests that this bound receptor.
process contributes to nCAM-mediated stimulation of
FGFR signalling, although this hypothesis remains to CAM signalling and the cytoskeleton
be tested. various studies in different cellular contexts Cadherins can recruit proteins that regulate small
support the notion that cell–cell adhesion is dispensable GTPases and the actin cytoskeleton to the cell mem-
for the nCAM–FGFR interplay. For example, nCAM brane. A typical example is p120 which, when it is free
forms a complex with FGFR on the surface of single cells, in the cytoplasm, is a powerful inhibitor of RHoA, as
resulting in constitutive FGFR activation34. Moreover, it acts as a RHoA guanine nucleotide dissociation-
the FGFR-binding motif and the modules involved in inhibitor (reviewed in REF. 16). However, p120 can also
homophilic interactions are located in markedly distant recruit the GTPase-activating protein RHo-guanine
regions of the nCAM ectodomain36,39. Therefore, cell– nucleotide exchange factor (p190RHo) to the cadherin
cell adhesion and FGFR-mediated signalling are distinct complex at the membrane, resulting in an extra level
and independent activities of nCAM, as experimentally of regulation of RHoA’s role in junction assembly and
demonstrated in different cellular models10,34. stability. The inhibition of RHoA by p120 can have
The neural Ig-CAM neurofascin provides another either a positive or a negative effect on cell motility.
example of ligand-independent modulation of FGFR on the one hand, it promotes actin reorganization at
signalling owing to its ability to associate with and stimu- the leading edge and de-adhesion at the trailing edge,
late the activation of FGFR1. This interaction does not but on the other hand, it reduces actin contractility in
require the extracellular region of the Ig-CAM itself 40, the cell body 44
thus supporting the notion that neurofascin-mediated Another protein that regulates the actin cyto-
cell adhesion is not a prerequisite for FGFR1 activation. skeleton, and therefore cell shape and motility, is
The adhesion-independent stimulation of FGFR1 is fur- α-catenin, which has been extensively studied. In
ther supported by recent studies on neuroplastin, which its monomeric state α-catenin binds to β-catenin
is an Ig-CAM that exists in two isoforms — nP65 and that is coupled to cadherin, but not actin. However,
nP55 — of which only nP65 can engage in homophilic homodimeric α-catenin binds actin and promotes
interactions and promote cell adhesion. nP55 binds to the bundling of actin filaments. Thus, the binding of
FGFR1 and induces FGFR-dependent signalling and α-catenin to the cadherin complex negatively regu-
neurite outgrowth41, thus confirming that adhesion is lates its activity on actin polymerization (reviewed in
dispensable for this function. REF. 14). These examples suggest that cadherins may
indirectly modulate actin organization by controlling
Adhesion‑independent inhibition of EGFR by DSG1. the availability of actin-binding proteins.
A striking example of adhesion-independent signalling several reports over the past few years have high-
was reported recently by Getsios et al.42, who studied lighted a causal role of l1 — a transcriptional target of
the role of the cadherin desmoglein-1 (DsG1; also the wnT family (hereafter wnT)–β-catenin pathway 45
known as DG1) in cell differentiation and morpho- — in enhancing the invasive and metastatic potential
genesis. In keratinocytes, DsG1 anchors adjacent cells of different cancer types, including colon carcinoma,
through adhesive structures called desmosomes and pancreatic carcinoma 46, ovarian carcinoma 47,48 and
also supports keratinocyte differentiation and supra- melanoma49. In many cases, a specific enrichment of
basal morphogenesis. A mutant version of DsG1 that l1 expression has been reported at the tumour invasive
lacks the amino-terminal ectodomain residues — and is front and in isolated disseminating cells. Furthermore,
therefore devoid of adhesive properties — is still able to the activation of the wnT–β-catenin pathway that is
induce keratinocyte differentiation. This effect is medi- associated with l1 upregulation has been observed
ated by the suppression of eGFR-mediated extracellular in single, migratory cells in culture45. Taken together,
signal-regulated kinase 1 (eRK1) and eRK2 activation, these findings indicate that intercellular adhesion is not
in agreement with the observation that this pathway required for the pro-malignant function of l1. Rather,
Desmosome maintains keratinocytes in an undifferentiated state43. such a function requires the interaction of l1’s cyto-
Protein complex that forms The mechanism whereby DsG1 inhibits eGFR signal- plasmic tail with the cytoskeleton-crosslinking protein
spot-like adhesive structures
that are randomly located
ling has not been clarified yet. However, DsG1 and ezrin50, an interaction that is likely to be regulated by
along the intercellular eGFR colocalize at the cell membrane, which suggests sRC kinases and has been implicated in the generation
boundaries. that they may be part of the same protein complex. of traction force51.

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REVIEWS

&QYPUVTGCO presence of wnT, the destruction complex is dis-

&QYPUVTGCO UKIPCNNKPI mantled and β-catenin is free to translocate to the
UKIPCNNKPI nucleus and modulate gene transcription through its
#EVKP
interaction with lymphoid enhancer factor (leF) and
T cell factor (TCF) family proteins, and other tran-
D E )TQYVJ F G scription factors (FIG. 1a). Therefore, the association
HCEVQT with cadherins at adherens junctions limits the nuclear
TGEGRVQT translocation of β-catenin. In addition, cadherins may
influence β-catenin signalling by promoting its deg-
+PVGITKP radation through a membrane-associated degradation
complex 55. Thus, cadherins can interfere with the tran-
C
scriptional activity of β-catenin not only by diverting it
+I%#/
away from the nucleus but also by increasing its degra-
'ZVTCEGNNWNCT dation at the membrane and augmenting the turnover
RTQVGCUG of cytosolic β-catenin. The cadherin–β-catenin inter-
2NCUOCOGODTCPG action is constitutive and may also occur in single cells
%[VQRNCUOKE in an adhesion-independent way 16,56.
+I%#/HTCIOGPV
H I similarly to β-catenin, cadherin may act as a mem-
brane trap for other proteins with transcriptional
&QYPUVTGCO 6TCPUETKRVKQP activity, such as p120 and plakoglobin. The pleiotropic
UKIPCNNKPI mediator p120 has multiple roles in cell biology (dis-
0WENGWU cussed below). At the transcriptional level, p120 binds
the transcriptional repressor KAIso and displaces it
Figure 4 | ectodomain shedding and nuclear function from promoters to inhibit transcription7,57. The tran-
0CVWTG4GXKGYU^/QNGEWNCT%GNN$KQNQI[
of ig-caMs. The action of extracellular proteases
scriptional activity of plakoglobin has not been studied
(mainly ADAM (a disintegrin and metalloprotease) family
members) results in the release of the soluble ectodomain
as extensively as that of β-catenin7,58. The effect of plako-
of various Ig-CAMs (immunoglobulin-like cell adhesion globin on gene expression can be positive, negative or
molecules) (a). These protein fragments can exert various neutral, depending on the cellular context. Although
biological activities, including the establishment of plakoglobin has been shown to bind to TCF/leF tran-
homophilic interactions (b), which can exert a regulatory scription factors and exert transcriptional activity,
role on cell–cell adhesion by displacing the interactions other reports have shown that the plakoglobin–TCF
with the cell surface-bound version of the Ig-CAM, the complex is unable to bind DnA7,59.
activation of growth factor receptors (c), the promotion Taken together, the data discussed above imply that
of integrin-mediated cell–matrix adhesion (d) and the cadherins may repress or induce gene transcription.
stimulation of integrin signalling (e). Ectodomain shedding
They do so in an unusual and indirect way, by binding
also results in the release of a cytoplasmic fragment that
could be capable of triggering signal transduction (f)
transcriptionally active proteins and retaining them at
and/or of translocating to the nucleus, where it might the membrane. notably, such binding can also occur
display transcriptional regulation properties (g). in the absence of adhesion, but it becomes more stable
upon the clustering of cadherins.

CAM proteolytic processing and signalling. several

Nuclear function of adhesion molecules proteases, including MMPs (matrix metalloproteases),
In parallel with their broad range of functions at the caspases and members of the ADAM (a disintegrin and
cell surface, an increasing body of evidence shows that metalloprotease) family, can cleave the intra cellular
CAMs are also able to influence nuclear processes, either domain of cadherins60–62. However, the biological func-
indirectly (for example, by regulating the nuclear traf- tion of the resulting cytoplasmic fragments is not fully
ficking of transcriptionally active partners) or directly understood. Recent data support the idea that a car-
(through their activities in the nucleus). boxyl terminus fragment of the cadherin desmoglein-2,
which is generated by Cys protease-mediated cleav-
Cadherins control β‑catenin‑dependent transcription. age, is pro-apoptotic63. Another report showed that
Certain adhesion molecules such as cadherins are able n-cadherin cleavage by ADAM10, which is induced
to control specific nuclear functions either indirectly by the transforming growth factor-β (TGFβ) family
— for example, by limiting the nuclear localization member bone morphogenetic protein 4 (BMP4), gener-
of transcription factors — or directly — for example, ates a fragment which increases β-catenin-dependent
after translocation into the nucleus. For example, one transcription64.
of the key players in wnT signalling is β-catenin52–54, These data support the concept that the cytoplasmic
which is constitutively bound to cadherins. when domain of adhesion molecules may also support signal-
β-catenin is released into the cytoplasm, it is quickly ling in the absence of the extracellular domain of the pro-
inactivated through phosphorylation and ubiquityla- tein. The cleavage may be induced by cell activation or
tion by a destruction protein complex that includes exposure to proteolytic enzymes and may not necessarily
axin and adenomatous polyposis coli (APC). In the require cell–cell contact.

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 REVIEWS

ADAMs and MMPs also cause the cleavage and ecto-

domain shedding of several Ig-CAMs, thus generating #EVKP
soluble ligands with various biological activities65 (FIG. 4).
For example, the soluble ectodomain of junctional adhe-
sion molecule C (JAM-C) has been reported to promote +PVGITKP
angiogenesis66. In certain cases, the released extracellu-
lar portion of Ig-CAMs is able to act as a soluble ligand
for growth factor receptors (FIG. 4c). The cleavage of the '%/
ectodomain (FIG. 4a) is often accompanied by the release
of the intracellular portion into the cytosol, and recent
observations implicate a role for these cytoplasmic frag- .
ments in important cellular functions. For example, upon
ectodomain shedding, l1 undergoes intramembrane #&#/
processing by γ-secretase, resulting in the release of a 2NCUOCOGODTCPG
γUGETGVCUG
soluble intracellular domain that enters the nucleus and
modulates the transcription of genes such as β3-integrin %[VQRNCUOKE
.HTCIOGPV
and cathepsin-B67 (FIG. 5). Although the cytoplasmic tail
βKPVGITKP
of l1 has also been shown to induce sRC-dependent %CVJGRUKP$
54%
activation of eRK1/eRK2 (REF. 68) (FIG. 5), this signalling
activity does not appear to be involved in l1-mediated
'4- 0WENGWU
gene regulation67. Rather, nuclear translocation of the l1
cytoplasmic tail requires interaction of its extracellular Figure 5 | Function of the l1 ectodomain and
Arg-Gly-Asp motif with integrins69, highlighting cross- cytoplasmic fragments.0CVWTG4GXKGYU^/QNGEWNCT%GNN$KQNQI[
Upon cleavage by ADAM10
talk between the extracellular and intracellular activities (a disintegrin and metalloproteinase 10), the ectodomain
of this Ig-CAM. of L1 (neural cell adhesion molecule L1) is released and can
Cytosolic and nuclear localization has also been support integrin-mediated cell adhesion and migration
observed for CD146 (also known as cell surface glyco- via αvβ5 integrin. Processing by γ-secretase releases a
cytoplasmic fragment that triggers SRC family kinase-
protein MuC18 and melanoma associated cell adhe-
dependant extracellular signal-regulated kinase 1/2
sion molecule) in endothelial progenitor cells (ePCs) (ERK1/2) signalling. In addition, the cytoplasmic L1
in sparse culture conditions, supporting the role of this fragment translocates to the nucleus and induces the
Ig-CAM in adhesion-independent signalling. However, transcription of specific genes, such as β3 integrin and
it is unclear whether the intracellular redistribution of cathepsin-B.
CD146 requires the cleavage of its cytoplasmic tail. In
particular, nuclear translocation appears to be a spe-
cific property of the short CD146 isoform, along with some of these activities are amplified by the cluster-
its redistribution to the leading edge of migrating ePCs. ing of adhesion molecules. Clustering is a consequence
The long CD146 isoform has a diffuse cytosolic pattern70. of the homophilic interaction between CAMs and, as
The different localization of the two isoforms seems well as strengthening adhesion, promotes the interaction
to underlie different functional properties, with short of membrane and intracellular partners such as growth
CD146 promoting ePC migration and proliferation and factor receptors, kinases, proteases or phosphatases that
long CD146 being involved in the subsequent stabili- may amplify signal transduction. An interesting question
zation of capillary structures. The nuclear localization is whether clustering of adhesion molecules may transfer
of short CD146 is also accompanied by increased pro- signals in the absence of adhesion. This is a common
duction of angiogenic cytokines70, although it remains feature of several other biological systems such as, for
elusive whether this reflects a role for nuclear CD146 in example, interaction of the notch ligand Delta-like pro-
modulating gene expression. tein 4 (Dll4) with its receptor, interaction of the ephrin
ligand with the ephrin receptor and interactions of Tyr-
Concluding remarks protein kinase receptor TIe 1 (TIe1) and TIe2 with
The concept that cell–cell adhesion molecules can prop- angiopoietins71–73. In these systems, cell–cell signalling
agate intracellular signals as well as maintaining adhe- only requires intercellular contacts, but molecular clus-
sion among cells is supported by solid evidence. In this tering helps to achieve optimal receptor–ligand inter-
Review we consider the possibility that these proteins action. These types of interactions may not promote, and
may have signalling properties in the absence of cell– do not necessarily require, adhesive activity.
cell contacts and adhesion. For instance, signalling by The possibility that CAMs could also propagate
intercellular adhesive proteins either within single cells intracellular signals when adhesion is prevented is not
or when the extracellular domain has been cleaved has just an academic question. For instance, in pathological
been described, and some examples are reported above. conditions such as cancer, the extracellular domain
In addition, CAMs may signal indirectly — for example, of CAMs may be partially or completely cleaved by
by bindingdifferent types of signalling proteins (such as the proteases that are present in high amounts in the
growth factor receptors, transcription factors or actin stroma. As discussed above, the remaining truncated
binding proteins), thus trapping them at the membrane. domain may still exert signalling activity and possibly

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© 2011 Macmillan Publishers Limited. All rights reserved

REVIEWS

modulate different cell functions such as growth or constitutively and also within single cells. Furthermore,
apoptosis. The type and amount of signalling may direct experimental systems are required to better deci-
be different from that mediated by the entire pro- pher the roles of adhesion and signalling, and to under-
tein. CAMs may also act indirectly by controlling the stand whether CAMs can act as bona fide biosensors of
localization of signalling proteins or transcription fac- the cell microenvironment even in the absence of their
tors to specific membrane domains. This may occur adhesive properties.

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Differential mechanisms of LEF/TCF family‑dependent outcomes of L1 proteolytic cleavage; the generation Acknowledgements
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Mol. Cell Biol. 20, 4238–4252 (2000). translocating into the nucleus and regulating the could not be discussed owing to space limitations. We are par‑
60. Vallorosi, C. J. et al. Truncation of the β‑catenin expression of specific genes, partially accounting ticularly grateful to F. Orsenigo for his help in preparing the
binding domain of E‑cadherin precedes epithelial for the pro-malignant role of L1 in tumours. figures of this manuscript. The work is supported by
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