TICB 1178 No.

of Pages 12

Special Issue: Quantitative Cell Biology

Review
Towards a Dynamic
Understanding of Cadherin-
Based Mechanobiology
Brenton D. Hoffman1,* and Alpha S. Yap2
Cadherin-based cell–cell adhesions are a primary determinant of tissue struc- Trends
ture. For several decades, it had been thought that the primary function of these Cadherin complexes bear mechanical
ubiquitous structures was to resist external mechanical loads. Here we review forces that arise from cellular contrac-
tility in adherent cells. Coupling to acto-
recent evidence that cadherins also couple together the force-generating acto- myosin via association with myosin-
myosin cytoskeletons of neighbouring cells, serve as potent regulators of the bound F-actin leads to contractile
actomyosin cytoskeleton, and activate diverse signalling pathways in response forces being applied to cadherins and
their associated proteins.
to applied load. In considering the force sensitivity of the molecular-scale
processes that mediate these events, we propose a dynamic picture of the Bond properties within the cadherin–
force-sensitive processes in cell–cell contacts. This quantitative and physical catenin complex influence mechano-
sensitivity of cadherin junctions. Catch
understanding of the mechanobiology of cadherin cell–cell junctions will aid bonds have been identified to mediate
endeavours to study the fundamental processes mediating the development adhesive binding between cadherin
ectodomains and the association of
and maintenance of tissue structure.
the cadherin–catenin complex with
F-actin.

Forces and Cadherin Junctions Functional responses to mechanical

A primary mechanical function of cell–cell adhesion is to resist detachment forces. This is stimulation of cadherin adhesions are
diverse and operate over substantially
exemplified by the classical cadherins, which have traditionally been thought to passively resist
different time scales. These include
large-scale forces arising external to the junctions, such as those associated with morphoge- changes in actin dynamics (operating
netic tissue movements (e.g., epiboly in the early embryo) or tissue stresses from external over minutes) and entry into the cell
loading due to gravity, muscle activity, or mechanical trauma [1–3]. This basic conceptual cycle (operating over hours).

framework has guided research in the field for many years. Recently, though, it has come to be
appreciated that the relationship between force and adhesion is more complex. A key insight is
that many of the forces that cadherins experience are generated by their host and neighbouring
cells [4–8], which can contribute to the tension that tissues display under physiological circum-
stances [9]. Cadherin adhesion thus serves to couple the contractile actomyosin cortices of cells
together [10]. Furthermore, cell signalling at cell–cell junctions can promote actin assembly and
myosin activation, leading to the active generation of contractility [11]. It is also increasingly
1
apparent that cells sense, interpret, and respond to those applied forces through a poorly Department of Biomedical
Engineering, Duke University, Durham,
understood process termed mechanotransduction [12,13]. NC 27708-0281, USA
2
Division of Cell Biology and
The application of force to junctions affects many aspects of their biological and mechanical Molecular Medicine, Institute for
Molecular Bioscience, The University
function. For instance, on the molecular scale, force is a key determinant of the strength of of Queensland, Brisbane QLD 4072
cadherin–cadherin interactions as well as the composition of cell–cell adhesions [14–16]. On Australia
larger length scales, this leads to the emergence of tissue level tensions that are at least partially
driven by actomyosin contractility within the constituent cells [8,9]. Such tension contributes to
*Correspondence:
morphogenetic events such as cellular rearrangements and cell extrusion. Thus, the active brenton.hoffman@duke.edu
generation, transmission, and sensing of mechanical forces play integral roles in cadherin (B.D. Hoffman).

Trends in Cell Biology, Month Year, Vol. xx, No. yy http://dx.doi.org/10.1016/j.tcb.2015.09.008 1

© 2015 Published by Elsevier Ltd.
 TICB 1178 No. of Pages 12

biology. Arguably, this is one of the major recent developments in our understanding of the cell
biology of these ubiquitous adhesion systems.

The realisation that cadherin junctions are mechanically sensitive structures implies that physical
principles guide and constrain the behaviour of these biological systems. In short, cadherin
junctions and the tissues that they support must obey quantitative physical laws and a
consideration of these laws can guide our understanding of their cell biology. In this article
we review recent developments important in our understanding of the mechanobiology of
cadherin adhesion systems. We first focus on molecular developments that reveal the important
roles that bond properties play in the biochemistry of cadherin complexes and discuss a range of
mechanosensitive biological processes that involve cadherin interactions. But this poses an
important challenge: molecular mechanisms and biological outcomes operate on vastly different
time scales that do not readily map to one another. Instead, there must be regimes that operate
on intermediate time scales to mediate between these two levels. How those intermediate time
scales arise is an important challenge for future research and we discuss some ways in which
this problem might be addressed through the application of quantitative and physical principles.

Force Sensitivity in the Cadherin Molecular Complex

Composition of the Cadherin Molecular Complexes
Classical cadherins function as membrane-spanning macromolecular complexes. The cadherin
ectodomains mediate adhesive binding between cadherins presented on neighbouring cells,
while the cytoplasmic tails interact with many cytoplasmic proteins. The best-understood
cadherin-interacting proteins are the catenins (b-, /-, and p120), which form a stoichiometric
complex with classical cadherins (Figure 1A). However, it is clear that this minimal cadherin/
catenin complex can interact with many other cytoplasmic proteins. Recent efforts to identify the
interactome of cadherins, using proximity biotinylation techniques [17], identified hundreds of
potential proteins and interactions [18,19]. While many of these interactions have yet to be
validated, these observations suggest that the biology of cadherins arises from the precise
network of interactions that are engaged in any particular context.

(A) Figure 1. The Mechanobiology of the

p120 Acn Cadherin–Catenin Complex. (A) The
Cadherin
catenin minimal cadherin–catenin complex that
mediates the mechanical coupling of the
actomyosin networks between neighbour-
ing cells. Localisation of cadherins to the
plasma membrane is regulated by p120–
β–catenin Plasma α–catenin catenin. Mechanical linkages between cad-
membrane herin and actin are mediated by b- and
/-catenin. (B) Zoom-in of left box shown
(B) in A. Diagram of the various conformations
that mediate cadherin–cadherin interac-
tions. The X-dimer conformation is thought
to be transient, but resists unbinding result-
ing from applied loads in certain regimes.
Unbound X-dimer Strand-swap The strand-swap conformation is more
dimer prevalent in mature adhesions, but is wea-
kened in response to applied mechanical
(C) Force loads. This conformation is mediated by the
exchange of strands containing conserved
tryptophan residues between the binding
cadherins. (C) Zoom-in of right box shown
in A. The binding interactions between the
Weakly Strongly cadherin–catenin and actin can be stabi-
bound sate bound sate lised by applied mechanical loads. This is
likely related to the ability of /-catenin to
undergo force-induced conformation
changes.

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Key Principles in Force-Sensitive Processes

Traditionally, mechanosensitive signalling has been regarded as a series of force-sensitive, switch-
like events [20]. Specifically, force-sensitive processes can be divided into four fundamental steps
(Figure 2). First, forces must be transmitted through specialised force-sensitive structures (mecha-
notransmission, Figure 2A). Often, increased mechanical loading of these structures causes a
force-induced change in the conformation of mechanosensitive proteins, enabling transduction of
the mechanical stimuli into a biochemically detectable signal (mechanotransduction, Figure 2B).

(A) Mechanotransmission Figure 2. The switch-like understand-

Force ing of force-sensitive processes in the
Vinculin cadherin–catenin complex. (A) First
forces must be transmitted to specialised,
Force load-bearing structures. (B) These loads
then induce conformation changes in cer-
tain proteins, often revealing new binding
VASP
sites for other proteins. The most under-
stood example of mechanotransduction in
the cadherin–catenin complex is the force-
induced conformation change exhibited by
(B) Mechanotransducon /-catenin. (C) To initiate signalling activ-
ities, the mechanically induced change
Force must be sensed. This is well described
Force by the ability of vinculin to bind to mechani-
cally loaded /-catenin. Once activated,
various signalling pathways can elicit sig-
nalling and cellular responses. These can
be divided into two categories: (D) quick
responses, such as the binding of existing
actin filaments, or (E) those that occur on
slightly longer time scales, such as the
(C) Mechanosensing assembly of new actin filaments through
the activation of VASP or other regulators
Force
of actin polymerisation.
Force

(D) Mechanoresponse
(Short mes)
Force
Force

(E) Mechanoresponse
(Long mes)
Force
Force

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Mechanical loading can alter molecular associations, ion channels, and even affect cytoskeletal
networks [20]. The detection of this signal (mechanosensing, Figure 2C), typically through forma-
tion of new protein–protein interactions, then elicits a response in a signalling pathway, gene
transcription, or cell behaviour (mechanoresponse, Figure 2D,E). Notably, mechanoresponses can
occur over a variety of time scales. These events are often treated as switch-like as there is no
accounting for the dynamics, or potential reversibility, within, or between, each step. Thus, in this
picture, if a strong enough force is applied, protein conformation changes are induced and
mechanoresponses are initiated. However, it should be noted that force-sensitive molecular
interactions are often allosteric [21], and it is their probability of residing in a particular conformation
that is biased by the application of force.

Mechanotransmission in the Cadherin Molecular Complex

We now know that cadherins bear force (Figure 2A). This is manifested at the mesoscopic level
by the recoil that occurs when adherens junctions are cut with lasers [9,22]. It has been
demonstrated at the molecular level for both E-cadherin [5,23] and VE-cadherin [4] using fusion
proteins of these cadherins that incorporate a Förster resonance energy transfer (FRET)-based
tension sensor (TS) [24]. Tension can also be detected in cadherin-associated proteins such as
vinculin, when engineered to incorporate a TS module [16], implying that force is transmitted
through the cadherin molecular complex. Tension at both the mesoscopic and molecular levels
is reduced when contractility is inhibited [5,22], confirming that it arises from mechanical
coupling of actomyosin to the cadherins. Beyond this fundamental phenomenology, the
important question is how forces acting upon cadherins can influence their function. In
particular, it is important to know how extensively force can be transmitted through the
cadherin–catenin complex and also how forces may influence the cadherin interactome. Early
answers to these questions have come from understanding how force affects the bond
properties of interactions within the cadherin molecular complex and how it can elicit cell
signalling events.

Impact of Force on Intermolecular Bonds of the Cadherin Molecular Complex

Force might affect cadherin adhesion if protein–protein interactions within the cadherin complex
were themselves sensitive to force. Formally, force can affect the strength of intermolecular
bonds in three possible ways [25]. Bonds may be insensitive to stress (ideal bonds); their
lifetimes may shorten with stress (slip bonds); or their lifetimes may increase in response to stress
(catch bonds). The physical basis of slip bonds is usually due to force-deforming proteins and
increasing the distance between interacting protein domains [26]. Catch bonds often arise when
mechanical loads cause conformational changes in proteins that lead to new interactions within
the protein–protein binding interface. Such force sensitivity has, indeed, been identified in the
adhesive binding of the cadherin ectodomain itself [27] and in the interactions between
cadherins and the actin cytoskeleton [21].

The crystal structures of a number of classical cadherins indicate that isolated cadherin
ectodomains can adopt either of two distinct trans-binding interactions [28,29] (Figure 1B).
In one conformation, opposing cadherins insert a conserved tryptophan residue into a hydro-
phobic pocket in their binding partner generating a strand-swapped dimer. In the second
conformation, extensive interactions between the N termini of the ectodomains yield an X-dimer
[30]. The X-dimer is thought to be an intermediate stage towards generating the strand-
swapped dimer. Interestingly, E-cadherin mutants that favour the X-dimer displayed adhesive
bond lifetimes that increased when force was applied [27,31]. Thus, X-dimers have features of
catch bonds, whose ability to strengthen in response to force would be predicted to allow initial
bonds to resist tensile force and thereby stabilise cell–cell interactions. However, the strand-
swapped dimers, which are thought to be more prevalent in mature adhesions, mediate longer
interactions at no or low forces compared with the X-dimer configuration [27]. Together, these

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data suggest that the X-dimer plays a role in stabilising nascent linkages, while strand-swap
dimers may mediate force-enhanced dynamics to enable cell rearrangements at large loads. At
high loads strand-swapped dimers of E-cadherin also displayed slip bond-like properties [27],
implying that other mechanisms, such as cadherin clustering, might be necessary to stabilise
junctions under high load [32–35].

Force sensitivity also influences the bonds between cadherins and the actin cytoskeleton.
Extensive biological evidence indicates that cadherins mechanically interact with actin filaments
[10,22,36,37]. This association was often thought to entail /-catenin, which can bind directly to
F-actin. However, a long-standing conundrum arose when minimal cadherin–catenin com-
plexes reconstituted from purified components failed to bind F-actin [38,39]. This issue has now
been resolved by the demonstration that the association between a minimal cadherin/catenin
complex and F-actin is force-sensitive (Figure 1C). Recently, single molecule optical tweezers
were used to show that applying force substantially increases the lifetime of interactions between
minimal cadherin complexes and actin filaments, an interaction which required /-catenin.
Kinetic modelling was consistent with a system where the cadherin/catenin–F-actin interaction
represented a two-state catch bond [21]. Catch bonds may then represent a common mecha-
nism that reinforces the physical and mechanical coupling of cadherin adhesion to the cyto-
skeleton upon application of force.

Mechanotransduction and Mechanosensing by Cadherin Adhesion Complexes

The impact of force on the molecular mechanisms of cadherin adhesion extends beyond the
bond properties of its constituent molecules. Transmitted forces ultimately impinge upon force-
sensitive proteins or protein complexes, causing biochemically detectable changes. Thus,
detection of mechanical load by a biochemical signalling network can be divided into two parts:
the direct transduction of mechanical forces into a biochemical signal, and the subsequent
sensing of this signal. For cadherin systems, mechanotransduction is currently best under-
stood to entail force-induced changes in the conformation of /-catenin (Figure 2B,C). It is
increasingly apparent that /-catenin can exist in a closed state that undergoes a conforma-
tional change upon mechanical loading to reveal cryptic binding sites for other proteins, such as
vinculin [40,41]. Mechanosensing is then accomplished through the force-sensitive binding of
such associated proteins. A newly developed FRET probe was recently employed to show that
/-catenin underwent conformational changes when force was applied to cadherin adhesions
by twisting magnetic beads coated with cadherin ligands [42]. Moreover, application of tensile
force could cause a purified /-catenin fragment bearing the vinculin-binding site to unfold and
bind vinculin, which, in turn, prevented refolding of this /-catenin fragment [43]. Thus, the
conformational changes elicited by force could generate cooperative effects to stabilise the
/-catenin–vinculin interaction. However, it should be noted that these experiments used a
truncated form of vinculin that is constitutively ‘active’ and which can stabilise integrin-based
focal adhesions, even when actomyosin contractility is inhibited [44]. Additional levels of
regulation may then influence the dynamic localisation of full-length vinculin molecule to
cadherin complexes.

There are likely to be many other force-sensitive proteins within adherens junctions. Proteins
such as /-actinin [45] and formins [46] that are found at cadherin junctions have been reported
to show force sensitivity [47,48], although in other contexts. It is also possible that both force-
sensitive and force-insensitive interactions exist at junctions. For example, although the associ-
ation between vinculin and /-catenin appears to require the application of force [40,41,43],
vinculin can also bind to b-catenin [15]. Whether this latter association is modulated by force
remains to be determined, but it raises the interesting possibility that the incorporation of some
proteins into cadherin complexes may be tuned by force, rather than be an all-or-nothing
phenomenon.

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Cadherin-Dependent Mechanoresponses
The cellular processes that respond to cadherin mechanosensing are only just beginning to be
characterised, but they appear to encompass diverse phenomena that operate on fairly
disparate time scales (Figure 2D,E). When analysed on short time scales (seconds–minutes)
cadherin mechanotransduction most evidently affects dynamic processes of the junctional actin
cytoskeleton. These processes often result in adhesion strengthening, or the mechanical
reinforcement of the load-bearing structure (i.e., the adherens junction). For example, the
recruitment of vinculin to cadherin junctions via its association with /-catenin is force-sensitive
[40] (Figure 2D). Activated vinculin can bind F-actin directly [49], which likely provides additional
linkages to reinforce cadherin–actin binding in response to force [50]. On slightly longer time
scales (tens of seconds to tens of minutes), load-bearing structures can also be reinforced
through enhanced assembly. Vinculin can recruit proteins of the Ena/VASP family, which
promote barbed-end growth of actin filaments to support junctional actin assembly [16], to
the adherens junction in response to applied loads (Figure 2E). There are likely to be many other
mechanisms that contribute to adhesion strengthening in different ways, as several other
proteins have been implicated in the maintenance of cell–cell contacts [51,52].

On very long time scales (hours), cadherin mechanosensing can potentially influence processes
such as single [53] or collective [54] cell migration, and mitotic spindle orientation [55,56]. These
are known to be influenced by tissue mechanics and require cadherins. However, whether they
are linked by cadherin mechanotransduction remains to be directly tested. If so, they are likely to
involve signalling pathways that act over longer time scales than those that influence the dynamic
junctional cytoskeleton. This is exemplified by the recent demonstration that MDCK monolayers
were induced to enter the cell cycle and proliferate when subjected to mechanical strain over
time courses of hours. This was attributable to the activation of Yap1 and canonical b-catenin
signalling through mechanisms that were perturbed by expression of a dominant-negative
E-cadherin mutant [57].

Molecular Scale Dynamics in Cadherin Mechanobiology

The traditional switch-like understanding of force-sensitive processes assumes that once a
sufficiently large load has been applied, all the subsequent steps will occur. This level of
understanding is likely sufficient for explaining phenomena where mechanotransduction is tightly
coupled to mechanosensing and key sensing elements diffuse and interact quickly. However, a
dynamic understanding of these processes is needed at longer time scales due to the underlying
force-sensitive dynamics of the cadherin–catenin complex as well as the existence of feedback
mechanisms.

The importance of considering a role for dynamics is well illustrated by two sets of observations.
First, protein linkages in cell–cell adhesions are dynamic. In single molecule measurements, both
cadherin–cadherin linkages and the linkages of cadherin complex with actin last at most several
seconds [21,25]. While in cells these linkages appear somewhat longer lived, potentially due to
the stabilising effects of interactions not present in the single molecule experiments, the
structures are still dynamic, as indicated by both fluorescence recovery after photobleaching
(FRAP) [39,58] and optical highlighting techniques [59]. Thus, even mature junctions exhibit
dynamics and display a steady-state turnover of constituent proteins. A second example comes
from the recent observation that while force-dependent conformational changes in /-catenin
were detected almost instantaneously after the application of load (<5 s), its binding partner,
vinculin, was recruited at a rate that was approximately six times slower [42]. Neither the
presence of continuous molecular dynamics within nor the separation of time scales associated
with mechanotransduction, for example, the conformation change in /-catenin, and mecha-
nosensing, for example, vinculin binding, fit with a switch-like model for force-sensitive pro-
cesses. Instead these data imply that on the molecular level, the mechanobiology of cadherin

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 TICB 1178 No. of Pages 12

adhesions is mediated by a network of dynamic, reversible, and force-sensitive protein–protein

interactions (Figure 3).

Physical principles and quantitative measurements can be used to reveal key aspects to
understanding how dynamics contribute to cadherin mechanobiology. One such insight is that
duration of mechanical signalling will be influenced by the effect of force on the mechanical

Force induced disassembly

Acn severing
protein

Force Force
Mechanotransmission

Mechanotransducon

Force Force

Mechanosensing
Force Force

Mechanoresponse
(Short mes)

Force Force

Mechanoresponse
(Long mes)

Force Force

Stable reinforcement

Figure 3. A Dynamic Picture of the Mechanobiology of Cadherin–Catenin. Transmission of forces through the
cadherin–catenin complex will be limited by the ability of the molecular constituents to resist applied loads. Thus, while force
can catalyse force-activated protein conformation changes and cell signalling events (shown in the right branch), it will also
enhance the rates of force-induced bond disassociation in the case of slip bonds and in certain force regimes in catch–slip
bonds (shown in left branch). Thus, there is an implicit competition between the termination of mechanotransmission and in
the initiation of mechanosensitive signalling in loaded cadherin–catenin complexes. Notably, force-induced dissociation
could happen through several distinct processes, which are shown within in the dashed box.

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linkages within the cadherin complex (Figure 3). On a molecular level, mechanotransmission is
dictated by the ability of protein–protein interactions to resist mechanical loading. In the extreme
case, breaking any link in a mechanotransmission pathway will terminate the mechanical signals
and cause any mechanosensitive proteins to revert to their unloaded state [43]. A key issue is the
location where breakages may occur in the cadherin–catenin complex. Measurements of the
affinity between cadherin–catenin complex constituents in their unloaded configuration suggest
that the weakest link is between /-catenin and actin [39,60,61]. However, bond strength under
load can be very different [2_TD$IF]from that suggested by the equilibrium-binding affinities, especially in
the case of catch bonds. For instance, biotin–streptavidin interactions, thought to be among the
strongest noncovalent interactions in nature are slip bonds [62] and rupture more readily than
/5b1 integrin and fibronectin interactions [63], which are catch bonds [64]. Based on the multiple
break points found in focal adhesions [65,66], we predict the existence of several positions for
force-induced dissociation of the cadherin–catenin complex (Figure 3). Additionally, while we
discussed these phenomena mostly in the context of an individual protein complex, cell–cell
contacts are composed of a large number of mechanosensitive linkages. Thus, even small shifts
in the typical lifetime of a key protein–protein interaction, or within a subpopulation of molecules
engaged in this interaction, could have significant consequences at the cell or tissue level.

Regardless of the exact molecular details, there is likely to be an innate competition between
mechanotransmission and the subsequent steps in force-sensitive processes. This can be
understood through an evaluation of time scales associated with these processes. If load can be
maintained on time scales longer than those associated with mechanotransduction and sensing,
which are likely dictated by protein diffusion and binding kinetics, then force-sensitive responses
will be initiated. This scenario is depicted in the right branch of Figure 3. Shown in the left branch
are the consequences of the rupture of a mechanical linkage, which leads to the unloading of the
complex and the termination of force-sensitive signalling. Notably, the sequence of events
depends on the exact rates of unbinding and the effect of force on these rates. As many bonds
are actually catch–slip bonds, strengthening at low forces and then weakening at larger forces
[25], applied load could be expected to either enhance assembly or disassembly of cadherin
adhesions in various contexts. These time scale-dependent effects could be particularly impor-
tant in mediating differential response to time-dependent mechanical stimuli, such as the forces
exerted on the vessel wall during blood flow or generated by a beating heart [20].

Emergence of Mechanical Feedback through Force-Sensitive Signalling

The impact of dynamics is likely to be even more pronounced for understanding multicellular
interactions and tissue level phenomena, which occur on much longer time scales, from minutes
to days. This is exemplified by evidence that force can activate signalling pathways that mediate
rearrangements in both the actomyosin cytoskeleton and the cell–cell contacts. Interestingly, the
changes in these two structures are often linked (Figure 4) and, like the molecular scale
responses described earlier, applied forces can cause context-dependent reinforcement or
disassembly of these structures. For example, E-cadherin is recruited to junctions in response to
local myosin activation and cellular force generation [67–69]. However, force can also cause
the cadherin content of junctions to be downregulated, either when cadherins diffuse away from
the junction or are internalised by endocytosis [70]. In mature epithelia, external loading can
promote junctional disassembly through endocytosis [58], while in endothelia, a balance
between Rho and Rac signalling regulates VE-cadherin dissociation from junctions [59]. Clearly
the mechanical state of the actomyosin cytoskeleton can potently regulate cadherin dynamics,
but the exact effects are likely context-dependent.

Similarly, cell–cell contacts can have diverse effects on the actomyosin cytoskeleton. For
instance, applied loads at cell–cell junctions often result in the enhanced stabilisation [71] or
assembly of actin [16] or of non-muscle myosin II [14] junctions. Conversely, applied loads can

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 TICB 1178 No. of Pages 12

Figure 4. Force-Induced Dynamics of

[1_TD$IF]Cell–[1_TD$IF]Cell Contact. Similar to individual
cadherin–catenin complexes, applied
Myosin forces can have diverse effects on the
cell–cell contact as a whole, leading to
either enhanced assembly or disassembly
in a particular context. Notably, fluctua-
tions in degree of engaged cadherin–
catenin complex changes in a correlated
manner with the degree of the assembly of
the actomyosin cytoskeleton. These com-
plex dynamics likely allow for cell adhesion
to enable cell rearrangements in some
contexts while reinforcing mechanical lin-
kages in others.

Force-induced
disassembly

Cadherin
delivery
Actomyosin
assembly

Actomyosin
disassembly

Cadherin
removal

Force-induced
assembly

also induce the disassembly of actomyosin networks. Such stress-induced actin turnover is
acutely influenced by the state and organisation of the actin filaments [72]. Compressed or
buckled actin filaments are more likely to undergo spontaneous fragmentation than unloaded or
tensed filaments [73], while myosin activity preferentially disassembles branched actin networks
[74], compared with bundled networks. Indeed, stress-induced actin turnover can limit the
forces that can be generated in cell–cell contacts [75,76]. In the latter case, branched actin

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networks found at lateral cell–cell junctions were preferentially affected by myosin-induced Outstanding Questions
contractility, whereas the bundled networks found at the apical zonulae adherentes were What other mechanical linkages within
relatively protected. Therefore, the cytoskeletal responses to junctional loads are likely to be cadherin junctions are force-sensitive?
Cadherin and /-catenin adhesive
complex and influenced by the organisational state of the actin networks that are bearing load, bonds are unlikely to be the sole
as well as the magnitude of that load itself. force-sensitive linkages in the cadherin
adhesome.
The effects of these rearrangement processes on force-sensitive signalling can be subtle, but
What signalling pathways are sensitive
may influence how long key pathways are active within cell–cell contacts. Epithelial monolayers to cadherin mechanotransduction?
can rapidly dissipate extrinsic stresses [55,56] and mechanisms that reduce load will tend to The induction of signalling resulting
terminate mechanical signalling, acting over time scales that would reflect how quickly load is from conformation changes in /-cat-
enin is unlikely to be the only force-
altered. This may occur by the dispersion of loads across reinforced scaffolds that bear the load
sensitive event capable of initiating
or the biochemically regulated decoupling of mechanical linkers. Specifically, the force-sensitive downstream signalling.
accumulation [67] or oligomerization [35] of adhesion receptors might be predicted to distribute
the stresses at those junctions, potentially unloading force-sensitive proteins that are found How do molecular mechanisms for
cadherin mechanotransduction inter-
there. Consistent with this idea, the molecular tension across E-cadherin was found to be
act across various time and length
constant between junctions that displayed varying cadherin intensity and mechanical load [69], scales to enable emergent, tissue level
implying that variations in the forces across cell–cell contacts are controlled by local accumula- morphogenetic events?
tion of E-cadherin, instead of differential loading of these proteins. Cadherin accumulation and
Does mechanical stimulation ultimately
adhesive strengthening may then constitute a mechanism that tends to limit the duration of affect cell signalling through local
mechanical signalling. mechanical feedback that is mediated
through cadherin mechanotransduc-
One important unanswered question is the identity of key factors that determine if an applied tion? Cadherin mechanotransduction
responds to contractile events gener-
load results in reinforcement or disassembly of cell–cell contacts. One possibility is that the ated within neighbouring cells. Can
resting tension within a cell–cell contact may dictate these responses. For example, the actin these local events form an intercon-
assembly necessary for junctional actomyosin and contractility [77] is itself tension-sensitive, nected network that couples adhesion,
signalling, and contractility resulting in
being decreased when myosin was blocked and increased when contractility was stimulated
emergent properties that are evident at
[16]. Taken together, these observations suggest the hypothesis that when cell-generated the tissue level?
forces are low, applied forces can be supported for time scales long enough to initiate signals
that enhance assembly of the junction. By contrast, if cell-generated forces are high, applied
loads cannot be supported for sufficient times, force-sensitive stabilisation pathways are
therefore not activated, and ultimately disassembly of cell–cell contacts occurs. Competition
between these processes may ultimately serve to return the system towards its set point and
promote mechanical homeostasis.

Concluding Remarks
The ultimate goal of most studies of cadherin mechanobiology is to identify the principles that
determine tissue structure (see Outstanding Questions). Major progress has come from the
realisation that many morphogenetic events are driven by actomyosin-based contractility that
is coupled to cadherin-based cell–cell junctions [78]. These include common, conserved pro-
cesses such as tissue invagination [79] and cell intercalation during convergent-extension move-
ments [80], which entail forces that are generated by pulsatile apical actomyosin networks [7,81].
Here we suggest that a dynamic understanding of cadherin mechanobiology may provide a clearer
insight into these processes. Overall, it is possible to regard the response to force of adhesion and/
or its associated cytoskeleton as a form of mechanical feedback [82], which will ultimately influence
mechanical signalling as has recently been observed in studies of cell intercalation during Dro-
sophila melanogaster germband extension [83]. It is likely that further work focused on integrating
the advances discussed in this review with optical techniques capable of detecting force-activated
protein dynamics, conformation, and biochemical activity (e.g., FRAP, FRET, and optical highlight-
ing) will be important to building a complete picture of how biological forces promote tissue
structure. As cancer and atherosclerosis are associated with alterations in tissue structure, it is
possible that defects in the dynamic force-sensitive feedback mechanism are associated with the
onset of these and other such force-sensitive diseases.

10 Trends in Cell Biology, Month Year, Vol. xx, No. yy

 TICB 1178 No. of Pages 12
Acknowledgments
B.D.H. is supported by a Searle Scholars Award, a Basil O’Connor Starter Scholar Award from the March of Dimes, and a
CAREER Award from the National Science Foundation. A.S.Y. is supported by the National Health and Medical Research
Council of Australia (1044041, 1037320).
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