Biochem. J. (2011) 436, 213–224 (Printed in Great Britain)
213
doi:10.1042/BJ20110217
REVIEW ARTICLE
The Hippo pathway and apico–basal cell polarity
Alice GENEVET and Nicolas TAPON1
Apoptosis and Proliferation Control Laboratory, Cancer Research UK, London Research Institute, 44 Lincoln’s Inn Fields, London WC2A 3LY, U.K.
The establishment and maintenance of apico–basal cell polarity is
a pre-requisite for the formation of a functioning epithelial tissue.
Many lines of evidence suggest that cell polarity perturbations
favour cancer formation, even though the mechanistic basis for
this link remains unclear. Studies in Drosophila have uncovered
complex interactions between the conserved Hpo (Hippo) tumour
suppressor pathway and apico–basal polarity determinants.
The Hpo pathway is a crucial growth regulatory network
whose inactivation in Drosophila epithelial tissues induces
massive overproliferation. Its core consists of a phosphorylation
cascade (comprising the kinases Hpo and Warts) that mediates
the inactivation of the pro-growth transcriptional co-activator
Yki [Yorkie; YAP (Yes-associated protein) in mammals]. Several
apically located proteins, such as Merlin, Expanded or Kibra,
have been identified as upstream regulators of the Hpo
pathway, leading to the notion that an apical multi-molecular
complex modulates core kinase activity and promotes Yki/YAP
inactivation. In the present review, we explore the links between
apico–basal polarity and Hpo signalling. We focus on the
regulation of Yki/YAP by apical proteins, but also on how
the Hpo pathway might in turn influence apical domain size as
part of a regulatory feedback loop.
INTRODUCTION
known as the ZA (zonula adherens). Apical to the ZA lie the
subapical region and the free apical surface, composed of densely
packed microvilli. Just below the ZA sits the septate junction,
the functional equivalent of the mammalian TJ, which provides
a permeability barrier and constitutes the start of the basolateral
domain. The apical domain is characterized by two main polarity
complexes: the aPKC (atypical protein kinase C) complex, and
the Crb (Crumbs) complex (see Figure 1 for details). The AJs are
mainly composed of homophilic Drosophila E-cadherin transdimers, and of the adaptor proteins Arm (Armadillo; homologue
of β-catenin) and α-catenin [1]. Two main groups of polarity
proteins are present at the septate junctions and are required for
their proper formation, although they appear to act independently
of each other to maintain the basolateral domain: the Scrib
(Scribble) module, which comprises Scrib, Dlg (Discs-large) and
Lgl [lethal(2) giant larvae] [5], and the recently characterized
Yurt/Coracle group [6,7]. Mutual antagonism between apical and
basolateral complexes was found to be key to the establishment
and maintenance of separate membrane domains [8,9]. For
example, aPKC phosphorylates Lgl, causing its dissociation from
the membrane, whereas Lgl promotes the disassembly of the
aPKC complex [10 –15]. The antagonism between the polarity
complexes defines the position and assembly of the AJs and
septate junctions, thus apico–basal polarity is crucial to the
establishment of cell–cell contacts [1,4].
Epithelia, cellular sheets that act as barriers between two
environments, fulfil a variety of functions in animals and are
the primary tissues of origin of cancer. To perform their function
(barrier, absorption, secretion etc.), epithelial cells need to adhere
cohesively to each other and to co-ordinate their behaviour. This
can only be achieved through the establishment and maintenance
of cell polarity, which is critical for generating robust cell–cell
contacts.
The apico–basal polarity machinery in Drosophila
Apico–basal polarity divides the cell into two complementary
membrane domains, an apical domain and a basolateral domain,
which are separated from each other by cell–cell junctions [TJs
(tight junctions) and AJs (adherens junctions) in mammals,
adherens and septate junctions in flies]. The separation between
these domains is achieved by the antagonistic action of the polarity
complexes, groups of proteins that define the apical and basal
regions and determine the position of the junctions (Figure 1).
Many polarity proteins were initially identified through genetic
screens in Caenorhabditis elegans early embryos or flies. The
present review mainly focuses on Drosophila epithelia, but most
aspects of apico–basal polarity are conserved across species, with
some exceptions, such as the absence of TJs in insects [1–3]. The
differences in polarity between different tissues and organisms
are extensively reviewed in [4].
In Drosophila larval imaginal discs, sacks of epithelial tissues
that are the precursors of most adult appendages, the AJs are
linked with the underlying cortical cytoskeleton to form a belt
Key words: cell proliferation, epithelial cell polarity, Hippo
signalling, junction, scaffold, tumour suppressor.
Loss of polarity and tumour formation
Loss of polarity is a hallmark of cancer and can participate in
tumorigenesis through distinct routes [16,17]. First, epithelial
Abbreviations used: AJ, adherens junction; AMOT, angiomotin; aPKC, atypical protein kinase C; Arm, Armadillo; BMP, bone morphogenetic protein;
Crb, Crumbs; Dlg, Discs-large; Dpp, decapentaplegic morphogen; Ds, Dachsous; dSTRIPAK, Drosophila Striatin-interacting phosphatase and kinase;
Ex, Expanded; F-actin, filamentous actin; FERM, 4.1/ezrin/radixin/moesin; Fj, Four-jointed; Ft, Fat; Hpo, Hippo; Fz/Dsh, Frizzled/Dishevelled; ICM, inner
cell mass; Jub, Ajuba; LATS, large tumour suppressor; Lgl, lethal(2) giant larvae; Mer, Merlin; MOBKL1A, Mps One Binder kinase activator-like 1A; PALS1,
protein associated with Lin Seven 1; PATJ, PALS1-associated tight junction protein; PCP, planar cell polarity; PP2A, protein phosphatase 2A; RASSF,
Ras-association family; SARAH, Sav/RASSF/Hpo; Sav, Salvador; Scrib, Scribble; Ste20, Sterile 20; TGF-β, transforming growth factor β; TJ, tight junction;
TSG, tumour suppressor gene; Wts, Warts; YAP, Yes-associated protein; Yki, Yorkie; ZA, zonula adherens; ZO, zonula occludens.
1
To whom correspondence should be addressed (email [email protected]).
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Figure 1
A. Genevet and N. Tapon
Main polarity determinants in Drosophila imaginal discs and in vertebrates
Schematic diagram of the polarity complexes, as well as a table presenting the main polarity proteins, and their vertebrate orthologues. P, phosphorylation. For clarity, some components of the
junctions were not mentioned or drawn, including components of the mammalian TJs, such as transmembrane claudins, or ZO proteins. aPKC complex: aPKC, Par-6, Cdc42 (small GTPase)
and Baz (Bazooka; or Drosophila Par3). Rather than being a constitutive member of the aPKC complex, Baz is actually excluded from the apical domain by the combined activities of aPKC and
Crb [141,142]. This results in Baz basal displacement, which defines the apical border of the ZA. Crb complex: Crb, Sdt (Stardust), PatJ, phospho-moesin (active form of the FERM protein
moesin) and the spectrin cytoskeleton. Scrib module: Scrib, Dlg and Lgl. Although no direct physical interactions have been shown between Scrib/Dlg and Lgl, those three proteins interact
genetically and at least partially co-localize [143]. Yurt/Coracle group: Yurt (Yrt) and Coracle (Cor) (FERM proteins), NrxIV (neurexin-IV; transmembrane protein), neuroglian and Na + /K+ -ATPase.
In Drosophila , the aPKC complex is first recruited to the plasma membrane in a Cdc42-dependent manner [8,13]. Multiple protein–protein interactions occur between the aPKC and Crb complexes,
as well as phosphorylation of Crb by aPKC, leading to correct localization of both complexes [93,144]. Both are involved in ZA formation, through the regulation of AJ endocytosis and via Baz/PAR3
[141,145–149]. On the basolateral side, Yurt negatively regulates Crb [150], whereas Scrib, Dlg and Lgl work as a genetic module whose role is to prevent spreading of apical determinants to the
basolateral membrane [8,9,13,151]. Reciprocally, the Crb and aPKC complexes antagonize the Scrib group and prevent its accumulation at the apical membrane (see the text). DE-cad, Drosophila
E-cadherin; E-CAD, E-cadherin; NrxIV, Neurexin IV.
cell proliferation is repressed by proximity to neighbours, which
is sensed through cell–cell contacts. This allows replacement of
cells lost upon tissue damage, and maintains quiescence under
normal conditions. Loss of this contact inhibition mechanism
is a hallmark of cancer and occurs when cells fail to respond
to social cues [17]. Thus loss of epithelial polarity might
promote overproliferation partly through loss of cell–cell contacts.
Secondly, loss of epithelial architecture (epithelial–mesenchymal
c The Authors Journal compilation c 2011 Biochemical Society
transition) promotes a motile phenotype and therefore tumour
invasion and metastasis [18].
In breast or colon cancer, loss of polarized architecture is
usually the first sign of transformation. Can loss of polarity
therefore lead to cancer? Several lines of evidence suggest that
polarity determinants are inactivated during tumour formation
(reviewed in [19–21]). For example, Scrib and Dlg are degraded
upon targeting by the human papillomavirus E6 oncoprotein
Hippo pathway and cell polarity
Figure 2
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The Hpo pathway phosphorylation cascade in Drosophila
Schematic representation of the Hpo pathway in a fly epithelial cell. P, phosphorylation. A broken line represents a genetic interaction that is still molecularly unresolved. Main Hpo pathway
components and their protein domains are represented. A list of the core Hpo pathway components and their mammalian orthologues is also provided (grey box). LIM, zinc-finger-containing LIM
domain (protein–protein interaction); RA, Ras-association domain; NH, N-terminal homology region, mediates Scalloped (Sd)-binding to Yki; WW domain, protein–protein interaction domain that
preferentially binds proline-rich regions, including PPXY sites.
[22,23]. The LKB1 gene, which encodes a kinase (PAR4 in C. elegans) known to be involved in a nutritionally
sensitive cell-polarity pathway [24,25], is mutated in an inherited
cancer predisposition known as Peutz–Jeghers syndrome [26].
Furthermore, in Drosophila, scrib, dlg and lgl belong to the
class of neoplastic TSGs (tumour suppressor genes), whose lossof-function elicits massive overproliferation, as well as tissue
architecture and differentiation defects in imaginal disc epithelia
[27]. All of these results suggest that loss of polarity can promote
or facilitate tissue growth, but relatively little is known about the
mechanisms driving this growth. Below, we summarize recent
work suggesting that cell polarity may limit growth through the
Hpo (Hippo) tumour suppressor pathway.
Ds (Dachsous) (Figure 2). Inactivation of the Hpo pathway
induces accelerated proliferation, a delay in cell-cycle arrest and
resistance to developmental apoptosis. However, in contrast with
neoplastic TSGs such as scrib, hpo mutant cells are eventually
able to undergo terminal exit from the cell cycle and can
mostly differentiate into the appropriate structures. Thus the
Hpo pathway is generally classified as a hyperplastic tumour
suppressor pathway [27]. A series of studies has changed the
field’s perception of the pathway (for reviews, see [29–32]) and
has outlined a complex relationship between the Hpo pathway
and cell polarity. We will describe this new vision of the Hpo
pathway before examining how polarity and Hpo signalling may
regulate each other.
The Hpo pathway, a conserved hyperplastic tumour suppressor
network
A NEW VIEW OF THE HPO PATHWAY
The Hpo pathway is a conserved signalling network that is
central to the regulation of epithelial tissue size [28–30]. Hpo
signalling was mainly delineated using mosaic genetic screens for
TSGs in Drosophila, and considerable evidence now exists from
mouse genetics and human cancer studies that an orthologous
mammalian pathway fulfils a similar growth-restricting function.
The pathway comprises the core kinases Hpo and Wts (Warts), the
adaptors Sav (Salvador) and Mats (Mob as tumour suppressor),
the transcriptional co-factor Yki (Yorkie), as well as a number
of modulators, such as the cytoskeletal proteins Ex (Expanded)
and Mer (Merlin), and the atypical cadherins Ft (Fat) and
From a ‘simple’ phosphorylation cascade . . .
Core Hpo pathway components and their adaptor proteins
Until recently, the Hpo pathway could be viewed as
a straightforward phosphorylation cascade (Figure 2). The
upstream kinase Hpo [mammalian Ste20 (Sterile 20)-like;
MST1/2 in mammals], a member of the Ste20-like family of
serine/threonine kinases, is thought to become active either
through auto-phosphorylation or the action of an unknown
kinase [28–30]. Active Hpo can then phosphorylate and activate
the NDR (nuclear Dbf2-related) serine/threonine kinase Wts
[LATS1/2 (large tumour suppressor 1/2) in mammals], which
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A. Genevet and N. Tapon
in turn phosphorylates the transcription co-activator Yki [YAP
(Yes-associated protein) in mammals]. This phosphorylation
inactivates Yki by inducing its retention in the cytoplasm by
14-3-3 proteins and thereby preventing its association with
its transcription factor partners, such as Scalloped (TEAD in
mammals), Homothorax or Teashirt [33–42]. Yki inactivation
leads to silencing of its target genes, which include pro-growth
and anti-apoptotic factors such as cyclin E, DIAP1 and the miRNA
(microRNA) bantam. Thus the Hpo pathway restricts tissue size
by antagonizing Yki’s function.
Two adaptor proteins, Sav and Mats, regulate the activity of
the core kinases Hpo and Wts. Sav directly binds Hpo, via a
C-terminal coiled-coiled region termed the SARAH domain [for
Sav/RASSF (Ras-association family)/Hpo], and can also bind
Wts via an interaction between its WW domains and PPXY
motifs in Wts [43–48]. Sav, which is itself a Hpo phosphorylation
target, potentiates Hpo-induced phosphorylation of Wts [43,45].
Similarly, Mats binds to Wts and potentiates its kinase activity
[49]. Furthermore, Mats is also a Hpo substrate and Hpophosphorylated Mats displays a greater affinity for Wts, leading
to an increase in Wts kinase activity [50,51]. Thus the core of
the Hpo pathway is composed of a kinase cascade in which the
upstream kinase Hpo, in co-operation with two scaffold proteins
Sav and Mats, activates the downstream kinase Wts, leading to
Yki inactivation.
Hunting for upstream regulators of the Hpo pathway
How Hpo activation is controlled to achieve the correct amount
of growth inhibitory signal has been a subject of much
interest in the field. By analogy to receptor tyrosine kinase
pathways, the search has been on for a Hpo pathway receptor.
The first upstream Hpo regulators to be identified were not
transmembrane receptors, but two adaptor proteins containing
a FERM (4.1/ezrin/radixin/moesin) protein–protein interaction
domain, Ex and Mer [52,53]. FERM domain proteins are believed
to act as membrane–cytoskeleton linkers by interacting both with
the plasma membrane and F-actin (filamentous actin) [54]. Ex and
Mer are two tumour suppressor proteins that co-operate to regulate
organ growth. They co-localize apically in vivo, heterodimerize
in vitro and are partially redundant [52,55]. Initial epistasis
experiments placed Mer/Ex upstream of the core kinases and
Mer/Ex overexpression was shown to promote Hpo/Wts activity in
cell culture [52]. Reciprocally, Mer and Ex also are transcriptional
targets of Yki, and are thus thought to be involved in a negativefeedback loop. However, until recently, no molecular relationship
between those upstream regulators and the core components
of the pathway (Hpo/Sav/Wts/Mats/Yki) had been established.
More recently, Ft and Ds, two atypical cadherins, were shown to
function as non-catalytic receptors for the pathway [56–59], and
these proteins will be discussed in the planar polarity section at
the end of the present review.
A change in perception of the Hpo pathway was initiated by the
finding that the upstream protein Ex directly binds the downstream
effector Yki [60,61], a result which blurred the distinction between
upstream and downstream components. This interaction is
mediated by PPXY motifs in Ex and the Yki WW domains,
protein–protein interaction motifs that preferentially bind prolinerich regions (including PPXY sites) [62,63] and PPXY motifs
in Ex. The Ex–Yki association participates in Yki inhibition
by sequestering it out of the nucleus, independently of its
phosphorylation status [60,61]. This mode of regulation was
recently shown to be conserved in mammals: the junctional
protein AMOT (angiomotin) and AMOT-like proteins sequester
c The Authors Journal compilation c 2011 Biochemical Society
YAP/TAZ (the Yki orthologues) out of the nucleus, through an
interaction between WW domains in YAP/TAZ and PPXY motifs
in AMOT/AMOTL1/AMOTL2 [64–67]. Similarly to Ex, AMOT
proteins can clearly antagonize YAP/TAZ through membrane
tethering, independently of the core kinase cascade, since nonphosphorylatable forms of YAP are still inactivated upon AMOT
overexpression [65–67]. In fact, the presence of a large number of
PPXY motifs in pathway members (three in Ex, one in Hpo and
five in Wts in the case of the Drosophila pathway) might act as a
‘magnet’, attracting Yki/YAP out of the nucleus [33,60,61].
AMOT appears to behave as Ex’s functional homologue,
tethering Yki/YAP to the apical membrane, although both proteins
share little sequence homology apart from their PPXY motifs.
The FERM-domain-containing FRMD6 is the mammalian protein
with most obvious sequence homology with Ex. Could Ex’s
domains, as well as functions, have become evolutionarily split
between AMOT and FRMD6? Is FRMD6 part of the mammalian
Hpo pathway or has AMOT ‘taken over’ Ex’s Hpo regulation
function? A detailed study of FRMD6 should answer these
questions. Analogously to Ex and AMOT, the AJ component
α-catenin has recently been reported to tether YAP to cell–cell
contacts in keratinocytes [68]. In this case, rather than directly
binding to YAP, α-catenin recruits 14-3-3, which in turn interacts
with phospho-Ser127 -YAP. It is not clear whether these tethering
mechanisms operate in parallel or if they display tissue specificity.
Other scaffold proteins have been identified as regulators of
the Hpo pathway. The WW-domain-containing protein Kibra was
recently found to promote activation of the pathway and interacts
with multiple components, ranging from upstream regulators Mer
and Ex to the core kinases Hpo and Wts and their adaptor protein
Sav, leading to pathway activation [69–71]. Drosophila RASSF,
which binds Hpo, and the LIM-domain-containing protein Jub
(Ajuba), which associates with Sav, Wts and possibly Yki, were
also identified as inhibitors of the Hpo pathway [72,73]. Such a
wide range of protein–protein interactions (Figure 3) complicates
the view of the Hpo signalling network and prompts a careful
investigation into the possible roles of these scaffolds.
. . . to the idea of a ‘super-complex’ that influences Hpo pathway
activity
As well as the cytoplasmic tethering discussed above, scaffold
proteins could regulate Hpo pathway activity by acting as bridges
between the core kinases and their substrates, thus increasing
the probability of phosphorylation events. However, there is no
evidence so far to support this notion. Indeed, the adaptor protein
Sav associates with Hpo and Wts, but whereas Hpo kinase activity
is increased in the presence of Sav, the Hpo–Wts interaction is not
affected [43,46]. Similarly, the adaptor protein Kibra associates
with Yki (A. Genevet, unpublished work) and Wts, but whereas
Wts kinase activity is diminished upon Kibra depletion, the extent
of the Wts–Yki interaction is not [70].
Another possibility is that binding to an adaptor might recruit
pathway regulators, thus influencing the enzymatic activity of the
kinases. This has been shown for RASSF, which binds to Hpo via
their respective C-terminal SARAH domains, leading to Hpo
inactivation [72]. This inactivation is at least in part due to the
association of RASSF with the dSTRIPAK (Drosophila Striatininteracting phosphatase and kinase) PP2A (protein phosphatase
2A) phosphatase complex, which can inactivate Hpo by dephosphorylating its T-loop [74]. This function of RASSF may
be antagonized by Sav, which competes with RASSF for Hpo
binding [72] and could therefore prevent Hpo dephosphorylation
by displacing the dSTRIPAK complex. The opposite mechanism
Hippo pathway and cell polarity
Figure 3
217
A new view of the Hpo pathway
Left-hand panel: the matrix of protein–protein interactions between components of the Hpo pathway, compiled from the literature. Right-hand panel: two views of the Hpo pathway: the successive
phosphorylation cascade (above), and the scaffolding machinery complex (below). For the sake of clarity, not all protein–protein interactions could be represented in the scaffold model. GST,
glutathione transferase; P, phosphorylation.
has been described for α-catenin, which prevents association of
YAP to PP2A, thereby preventing dephosphorylation on Ser127
and blocking YAP nuclear translocation [68].
Alternatively, interactions between different components of the
pathway could directly influence protein conformation. Those
conformational changes could for instance potentiate the activity
of the kinases themselves, or reveal/conceal phosphorylation
sites on their various substrates. For instance, binding of
phosphorylated MOBKL1A (Mps One Binder kinase activatorlike 1A; a Mats orthologue) to LATS1 (a Wts orthologue)
promotes LATS1’s ability to autophosphorylate on Ser909 ,
suggesting a change in conformation upon MOBKL1A binding
[51]. It is possible that Sav and its orthologue SAV (or WW45)
have a similar effect on Hpo/MST kinases. In addition, Mer exists
either as an active unfolded form or an inactive folded form,
whereby its C-terminal fragment folds on to its FERM domain,
partially masking it [75]. Ex, as a FERM protein, might behave
similarly, and reciprocal binding between Mer and Ex might
trigger their unfolding into active forms able to bind Hpo pathway
members with greater affinity [55]. Binding of Mer/Ex with
Kibra might promote their active open conformation, potentially
explaining why the Mer–Ex interaction is strengthened in the
presence of Kibra [70].
Furthermore, protein–protein interactions can affect the
stability of Hpo pathway components, as is the case for Sav
and RASSF, both of which are stabilized after binding to Hpo
[45,72]. Similarly, binding of LATS2 to mammalian KIBRA
appears to protect LATS2 from ubiquitin-mediated proteasome
degradation [76], which may be mediated by the E3 ligase
Itch [77,78]. Interestingly, phosphorylation of YAP on Ser381 by
LATS1/2 primes YAP for binding to the SCF (Skp1/cullin/F-box)
ubiquitin ligase and subsequent ubiquitination and degradation
[79], although this residue is not conserved in flies.
Finally, the Hpo pathway scaffolds could function as a platform
to bring the core components to their site of activity at the plasma
membrane, an issue that will be discussed in detail below.
In addition to the discovery of new adaptor proteins acting
as bridges between different components of the Hpo pathway,
a number of protein–protein interactions have recently been
uncovered between established members of the Hpo network.
Indeed, Mer and Ex were recently found to associate with Sav and
Hpo, which constitutes the first biochemical link between these
upstream regulators of the pathway and the core kinases [69].
Strikingly, Mer-bound Sav appears to be highly phosphorylated,
suggesting it may be associated with Hpo [69]. Thus it is now
clear that the interactions between Hpo pathway members are
complex, involving WW domains, PPXY motifs, SARAH and
FERM domains, as well as other protein–protein interaction
motifs (Figure 3). The extent of these protein–protein interactions
suggests the existence of a supra-molecular complex that controls
Hpo pathway activity, although the existence of such a complex
in vivo has not been proven. Indeed, most of the interactions
between Hpo pathway components have been described by coimmunoprecipitation experiments of overexpressed proteins and
should be interpreted with caution until they have been further
validated. In particular, the multiplicity of possible WW/PPXY
combinations between pathway members (Figure 2) makes it
difficult to assess which are relevant in vivo. Nevertheless, the
existence of a Hpo super-complex and its importance in pathway
regulation are likely to be areas of intense future investigation.
The apical domain as the site of Hpo pathway activity
The adaptor proteins Mer, Ex and Kibra co-localize in vivo and
are apically localized, similarly to Jub, which is located at the
AJs. As these scaffolds interact with Hpo, Sav, Wts and Yki,
the apical localization of the former would be expected to elicit
an apical localization of the latter. Accordingly, overexpression
of Ex, which directly binds Yki [60], leads to an increase in
apical Yki [60,61], whereas AMOT family proteins and α-catenin
promote YAP/TAZ junctional localization [64,65,68]. Under
normal conditions, Hpo and Wts appear mostly cytoplasmic
[56,80]. However, the existence of an apically localized pool
of Hpo was recently reported in eye discs [81], whereas a
significant portion of Mats is apically localized [82]. Finally,
a fractionation assay in cell culture revealed that a membranebound fraction of Hpo exists, which is reduced upon combined
c The Authors Journal compilation c 2011 Biochemical Society
218
A. Genevet and N. Tapon
depletion of Kibra, Mer and Ex [69]. Is this membrane fraction
the most biologically active? Indeed, forcing the apical membrane
tethering of MST1 by adding a myristoylation signal leads to
its activation [83]. Likewise, membrane tethering of Mats or its
vertebrate orthologue leads to Wts/LATS activation [51,82,84].
Finally, similar to Ex [70], AMOT proteins are required for
full YAP/TAZ phosphorylation since this decreases upon AMOT
depletion [65], suggesting that tethering of Yki/YAP/TAZ to the
junctions facilitates its phosphorylation. Thus multiple lines of
evidence point at apical membrane recruitment being an important
step in Yki inactivation by the Hpo pathway; but what is the link
between the apical membrane and Hpo pathway components?
REGULATION OF HPO SIGNALLING BY POLARITY COMPLEXES
The Crb complex connects Hpo signalling with polarity
Several recent Drosophila studies suggest that the apical
transmembrane protein Crb can influence Hpo signalling [81,85–
87]. Crb was found to bind Ex via an interaction between Crb’s
FBM (FERM-binding motif), situated in its short cytoplasmic
tail, and Ex’s FERM domain [85]. This association is required for
Ex apical localization. Hence, in crb mutant cells, Ex is basally
mislocalized, resulting in a down-regulation of the Hpo pathway
and consequently in overgrowth [81,85–87]. Mer or Ft were not
affected in this context, suggesting that Crb’s effect on Ex is
specific. These results provide the first direct connection between
a polarity protein and localization of a Hpo pathway member.
Interestingly, AMOT had previously been reported to associate
with TJ components, and in particular with the mammalian
orthologues of the Crb and aPKC polarity complexes such as
PATJ [PALS1 (protein associated with Lin Seven 1)-associated
TJ protein], PALS1 (the Stardust orthologue) and PAR3 [88].
Accordingly, the TJ fraction of YAP or TAZ was increased
upon AMOT overexpression [65]. As AMOT is required for
TJ maturation [88], its identification as a YAP/TAZ modulator
suggests that mature junction formation in itself might regulate
Hpo pathway signalling output. This notion is supported by
Varelas et al. [64], who showed that disruption of TJs in a
dense cell culture, through Ca2 + depletion or knockdown of
TJ components CRB3 or PALS1, elicited a down-regulation
of the Hpo pathway and YAP/TAZ nuclear accumulation. In
keratinocytes, both Ca2 + depletion and α-catenin knockdown
resulted in YAP nuclear accumulation, consistent with a role
for α-catenin in YAP cytoplasmic retention in the skin [68].
Further connections between the Hpo pathway and AJs/TJs exist:
mammalian MER [also called NF2 (Neurofibromin 2)] is required
for TJ maturation and links α-catenin to PAR3 [89], whereas PATJ
associates with KIBRA and TAZ through interactions between
PATJ’s PDZ domains and KIBRA’s or TAZ’s PDZ-binding motifs
[90,91]. In addition, YAP2 (one of the YAP isoforms) binds to
the TJ component ZO-2 (zonula occludens 2) via a PDZ domain,
although this interaction appears to favour nuclear translocation
rather than membrane retention [92].
Intriguingly, in Drosophila, not only Crb depletion, but also
its overexpression elicited a mislocalization of Ex and resulted
in massive overproliferation due to Hpo pathway inactivation
[81,85–87]. This phenotype might be due to a dominant-negative
effect of Crb overexpression. However, an interesting possible
explanation stems from the finding that Crb binding to Ex leads to
Ex phosphorylation and degradation [85,86]. Rather than simply
being a positive regulator of Hpo signalling, Crb may therefore
fulfil a dual role: both localizing Ex to the membrane where
it can sequester Yki and promote Hpo activity, and promoting
c The Authors Journal compilation c 2011 Biochemical Society
Ex degradation once it has signalled to shut down excess Hpo
signalling. Crb would then function as a buffer, allowing finetuning of Hpo signalling, but preventing excess activity. Several
interesting questions remain open. For instance, what is the kinase
responsible for Ex phosphorylation upon Crb binding? aPKC is
a candidate, as it is known to phosphorylate Crb [93]. Could Ex
phosphorylation (whether by aPKC or another kinase) prime it for
removal from the membrane and/or degradation? More research
is needed to answer these questions.
Other links between polarity complexes and Hpo signalling
In parallel, a study by Richardson and co-workers showed
that the polarity determinants Lgl and aPKC influenced Hpo
apical localization [81]. Overexpressing aPKC or loss of its
antagonist Lgl induced cytoplasmic mislocalization of an apical
pool of Hpo and increased co-localization between Hpo and its
negative regulator RASSF. Consistently, a down-regulation of
Hpo pathway signalling activity ensued. These results suggest
that aPKC can reduce Hpo pathway activation, a function that
is antagonized by Lgl, although it appears to be independent of
Crb and the mechanism therefore remains to be elucidated. The
newly discovered Hpo pathway regulator Kibra is an interesting
candidate in this context. Human KIBRA was identified as an
aPKC substrate [94], and the aPKC-binding region and one of
the phosphorylation sites are conserved in Drosophila Kibra.
aPKC could therefore reduce Hpo activation by phosphorylating
pathway scaffolds, such as Kibra and Ex, modifying their binding
affinities. Other basal polarity proteins such as Dlg or Scrib also
appear to influence Hpo pathway targets in ovarian follicle cells
[95].
Sensing social cues at the apical junctions
The emerging model is that the apical domain and cell–cell
junctions play a key role in Hpo pathway regulation. However,
what cues are being sensed through cell–cell contacts by the
Hpo pathway remains the most important question. An attractive
possibility is that the apical domain, and in particular the TJs/AJs,
might function not only as a membrane anchor for pathway
components but also as a signal-receiving platform for the Hpo
pathway to sense ‘social’ signals from neighbouring cells (e.g.
absence of neighbours or presence of an inappropriate neighbour).
In mammals, the Hpo pathway is a crucial mediator of contact
inhibition of proliferation [38,96,97] and is thus involved in
‘neighbour sensing’. At low cell density, YAP is mainly nuclear
and drives proliferation with its partner TEAD [38,97]. In
highly dense cell culture, YAP is phosphorylated on Ser127 and
sequestered in the cytoplasm, thus eliciting proliferation arrest
[97]. Furthermore, the timing of YAP translocation correlates
with TJ assembly, and YAP becomes nuclear at high cell density
upon depletion of CRB3, PALS1 or AMOT-like proteins [64,97].
Thus it appears that, through the CRB–AMOT complex, the Hpo
pathway uses TJs to sense the presence of neighbours. Indeed,
α-catenin, which tethers YAP at the AJs in skin cells [68], has also
been implicated in contact inhibition and functions as a tumour
suppressor in mouse skin [98,99]. Since loss of contact inhibition
is a hallmark of cancer, this mechanism is likely to represent
an important part of the Hpo pathway’s tumour suppressor
function. Even in tumours where the Hpo pathway has not directly
been affected by a genetic or epigenetic lesion, loss of tissue
organization, which is a characteristic of many tumours, may
cripple Hpo signalling through disruption of AJs/TJs and allow
the tumour to co-opt YAP/TAZ pro-growth and anti-apoptosis
activities.
Hippo pathway and cell polarity
Figure 4
219
A complex relationship between the Hpo pathway and apical polarity determinants
Left-hand panel: schematic diagram of the multiple protein–protein interactions identified between Hpo pathway components and polarity determinants in Drosophila and mammals. Right-hand
panel: schematic diagram summing up the multiple connections between Hpo pathway and polarity. The arrows do not distinguish between activating or inhibitory effects. Baz, Bazooka; DE-cad,
Drosophila E-cadherin.
In Drosophila, wild-type cells neighbouring crb mutant tissue
lose Crb expression along the border with the mutant cells,
possibly as a result of loss of trans-homodimerization [87]. This
loss of Crb then results in loss of Ex apical localization. Thus the
level of Crb in a cell can transmit information to the Hpo pathway
in a neighbour via Ex regulation. Crb could therefore conceivably
be a mediator of contact inhibition of growth. However, it is not
clear how the concept of contact inhibition in cell culture relates to
development in an epithelium, where cells are in constant contact
with their neighbours. Such ‘social’ sensing would nonetheless
become particularly relevant in situations of tissue injury, when
contact with a neighbour is lost or cell density dramatically
drops, thus allowing the Hpo pathway to participate in tissue
regeneration. Consistent with this idea, several studies recently
have uncovered a role for the Hpo pathway in adult intestinal
regeneration in Drosophila and mice [100–104], as well as in
Drosophila wing imaginal disc regeneration [105,106]. Tissue
injury elicited either through bacterial infection, toxic chemicals
or genetic cell ablation leads to a disruption of Hpo signalling, Yki
activation and proliferation of neighbouring cells to replace lost
tissue. This suggests that the Hpo pathway might indeed act as a
sensor of tissue damage, possibly through its ability to respond to
disrupted cell–cell contacts.
The relationship between polarity and Hpo signalling activity
is unlikely to be as simple as: polarized cell→Yki/YAP inactive,
non-polarized cell→Yki/YAP active. This is exemplified by
recent work in pre-implantation mouse embryos [40]. During
the first stages of embryonic development, YAP is nuclear in all
cells. However, at the blastocyst stage, when the mesenchymal
ICM (inner cell mass) and the epithelial trophectoderm are
specified (the former will form the embryo; the latter the
extra-embryonic tissues), YAP localization becomes spatially
regulated. Whereas polarized trophectodermal cells maintain
nuclear YAP, non-polarized ICM cells activate the Hpo pathway,
leading to translocation of YAP to the cytoplasm [40]. This Hpo
signalling activation could be due to the high density of the
ICM, which is enclosed inside the trophectoderm. It is, however,
unclear how mesenchymal ICM cells, which do not maintain
TJs [107], would be able to sense this high density and trigger
the Hpo pathway. Alternatively, the ICM could be subjected to
compression forces, which might activate Hpo signalling through
mechanotransduction.
Mechanical stimuli have been proposed to play a crucial role
in regulating growth arrest during development, in particular in
the fly wing imaginal disc [108,109]. Could the Hpo pathway
therefore respond to mechanical forces? The cell–cell junction and
the cytoskeleton play an important role in transducing mechanical
signals [110]. Interestingly, as well as being linked to junctions
as described above, the Hpo pathway shares several connections
with the actin cytoskeleton. First, Mer and Ex are FERM proteins,
many of which associate with actin filaments [7]. Secondly,
Jub, the recently discovered Hpo pathway inhibitor, belongs to
an actin-associated family of LIM-domain-containing proteins
[111]. Thirdly, AMOT has been shown to localize with F-actin
and to regulate actin stress-fibre formation [112]. As YAP directly
binds AMOT [65,67], a fraction of cytosolic YAP was found to colocalize with AMOT on cytoskeleton-like fibrous structures [65].
Finally, MST1/2 are associated with F-actin and mediate JNK
(c-Jun N-terminal kinase) signalling in response to cytoskeletal
disruption [113]. It is therefore plausible that the role of the apical
scaffolding machinery might be to relay physical stimuli, such
as tension or compression, to the Hpo pathway, although this
possibility has not yet been addressed.
To summarize, given the multiple connections between the
polarity complexes and Hpo pathway members (Figure 4), it is
tempting to speculate that, rather than merely providing a scaffold
for the assembly of the core Hpo kinase cascade, the polarity
machinery plays an active role in signalling, relaying extrinsic
(cell–cell contact, mechanical environment) or intrinsic (polarized
state of the cell) information to the pathway core.
REGULATION OF APICAL DOMAIN SIZE BY THE HPO PATHWAY
As well as being regulated by apically localized proteins, the
Hpo pathway appears in turn to influence apical determinant
distribution. Apical ‘bulging’ of wts mutant cells was one of
the first phenotypes observed by electron microscopy for a
Hpo pathway core member and was later noted in hpo mutant
tissue [43,114], suggesting a potential defect in apical domain
c The Authors Journal compilation c 2011 Biochemical Society
220
A. Genevet and N. Tapon
organization. Recent studies showed further that Hpo pathway
loss-of-function elicited a hypertrophy of the apical domain and
AJs correlated with an accumulation of apically localized proteins,
such as the Notch receptor and apical polarity proteins (aPKC,
Arm, etc.) [80,115]. Interestingly, in C. elegans, wts loss-offunction also induces mislocalization of apical components [116].
What causes this apical hypertrophy? Overexpression of some
apical determinants, such as Crb, can lead to apical membrane
accumulation [117], and such proteins could conceivably be Yki
targets. Indeed, loss of crb is sufficient to rescue the apical
protein accumulation [80,115], as well as the apical membrane
hypertrophy [115] induced by Hpo pathway loss-of-function.
However, as crb is not a clear direct transcriptional target of
the pathway, other Yki targets might be responsible for the
phenotype. Beside the excess transcription of apical determinants,
an imbalance between exocytosis and endocytosis might account
for the apical hypertophy of hpo mutant cells. Interestingly,
several pieces of evidence link the Hpo pathway to the regulation
of endocytosis. hpo mutant clones in ovarian follicle cells showed
increased bulk uptake of a lipophilic dye [118]. Combined loss of
ex and mer leads to a defect in apical clearance of Notch and other
surface receptors, suggesting a defect in endocytosis [119]. Future
studies should reveal whether vesicle trafficking defects underlie
the apical domain expansion upon Hpo pathway disruption.
What is the role of apical domain size regulation by the Hpo
pathway? We have outlined the importance of the apical domain
in regulating Hpo signalling activity. It is therefore tempting to
speculate that apical hypertrophy upon Hpo signalling disruption
might be part of a fail-safe negative-feedback loop in order to
re-establish Hpo activity when it is compromised. Indeed, Kibra,
Mer and Ex, three Hpo pathway apical scaffolds, are Yki targets
and are therefore up-regulated upon Hpo inactivation [52,70], as
was also recently shown for mammalian KIBRA [76]. Such a
feedback loop would ensure that Yki activity is kept in check
during development.
THE HPO PATHWAY AND OTHER FORMS OF CELL POLARITY
PCP (planar cell polarity)
Apico–basal polarity is not the only form of polarity in an
epithelium. Frequently, epithelial tissues also possess a form of
PCP, which allows cells in an epithelium to sense their position
in relation to the tissue axes (antero–posterior, dorso–ventral
or proximo–distal) and orientate themselves accordingly. An
example is the orientation of hair on the mammalian epidermis.
Two signalling pathways ensure the robustness of PCP: the Fz/Dsh
(Frizzled/Dishevelled) signalling pathway and the Ft pathway.
Some studies suggest that the Ft pathway acts upstream of the
Fz/Dsh pathway, whereas other evidence points to parallel roles
([120–122]; for a review, see [123]).
As mentioned above, the Ft signalling pathway is a major
upstream branch that regulates Hpo signalling activity [56–
59]. Ft forms trans heterodimers with Ds [124]. The Golgi
kinase Fj (Four-jointed) modulates the Ds–Ft interaction by
phosphorylating both the Ds and Ft extracellular domains [125–
128]. Fj and Ds are expressed in opposite gradients along the
proximo–distal axis of Drosophila limbs, thus resulting in a
proximo–distal gradient of active (Ds-bound) Ft, such that each
cell has more liganded Ft on its proximal than its distal side
[120,121,129]. This small difference in Ft activity is thought to
result in the planar polarization of the atypical myosin Dachs, the
membrane localization of which is antagonized by Ft, resulting
in Dachs localization on the distal side of each cell [130].
Active Ft signalling in turn influences the Hpo pathway, partly
c The Authors Journal compilation c 2011 Biochemical Society
by promoting Ex’s apical localization and partly by preventing
Dachs-dependent Wts degradation [56–59]. In both cases, the
molecular mechanisms underlying the Ft-mediated regulation of
Hpo signalling are still unclear.
What is the signal relayed to the Hpo pathway by the Ft–Ds
interaction? The ‘steepness hypothesis’ is an attractive model
which suggests that the Ft–Ds module allows the Hpo pathway to
‘read’ the slope of the long-range morphogen gradients that are
responsible for the growth and patterning of developing tissues
[131]. It is based on the idea that: (i) each cell in the developing
field of a tissue can sense the steepness of a linear morphogen
gradient and divide accordingly until the gradient slope falls below
a certain threshold; (ii) the steepness of the gradient decreases as
the tissue grows; and (iii) Ft signalling senses morphogen gradient
steepness and translates it into growth regulation (via the Hpo
pathway) and PCP, thus co-ordinating three major morphogenetic
processes: size, shape and patterning. Such a role for Ft–Ds
signalling was suggested by studies [132,133] showing that:
(i) disturbances in the gradient of the Dpp [decapentaplegic
morphogen; the BMP (bone morphogenetic protein)/TGF-β
(transforming growth factor β) orthologue] induced alterations in
the graded expression of Fj and Ds, suggesting that Dpp signalling
(directly or indirectly) controls Ds/Fj expression; (ii) that uniform
expression of Fj and Ds led to an overall reduced tissue growth;
(iii) that ectopic proliferation was induced in cells that were
exposed to (and able to sense) a sharp gradient in Ft–Ds activity
across their width; and (iv) that this ectopic proliferation was
mediated by triggering of Hpo pathway targets. Such positional
information sensing may explain the requirement for pathway
components in mediating the limb regenerative response in cricket
[134].
Although this model is extremely appealing, several important
issues remain to be resolved [131]. For example, how would
a cell be able to compare the difference of a few liganded Ft
molecules on its proximal against its distal size, and compute this
into Dachs planar polarization and a binary proliferation/arrest
response remains unclear. Through its ability to differentially
affect the Ds–Ft interactions (phosphorylation of Ds decreases
binding to Ft, whereas phosphorylation of Ft increases binding
to Ds) [127,128], Fj might play a crucial role in strengthening
this weak initial asymmetry, but some form of positive-feedback
regulation is also likely to be required. In addition, the relationship
between Ft and Dpp signalling appears to be more complex
than first envisaged. YAP and SMAD1, one of the transcription
factors effectors of BMP signalling, as well as their orthologues
Yki and Mad interact with each other, leading to transcriptional
regulation of a subset of common target genes (e.g. bantam in flies)
[135,136]. Furthermore, YAP/TAZ regulates SMAD2/3 nuclear
localization in response to cell density [64]. This suggests that the
Hpo and Dpp/BMP/TGF-β pathways are tightly intertwined at
the level of their downstream transcription factors rather than
Ft/Yki signalling simply being a growth control effector for
Dpp/BMP/TGF-β. An alternative view to the gradient steepness
hypothesis suggests that the Ft signalling and Dpp gradients act in
a complementary, but independent, manner to regulate growth in
the wing imaginal disc [137].
Polarity in cell migration
Migrating cells are also polarized, having a leading edge that
faces the direction of migration. Even though this type of polarity
is different from apico–basal polarity, it involves many of the
same polarity determinants. However, their relationships might
be different, as it appears that both the aPKC complex and the
Hippo pathway and cell polarity
Scrib module are required at the leading edge for cell migration
[138]. Since the Hpo pathway influences and is influenced by
apico–basal cell polarity, could it be implicated in migration?
Interestingly, mammalian KIBRA has been reported to interact
and co-localize with the polarity protein PATJ at the leading edge
of migrating podocytes [90]. Furthermore, KIBRA is required for
migration of NRK (normal rat kidney) cells, where it mediates
delivery of aPKC by the exocyst at the leading edge of migrating
cells [139]. In addition, YAP promotes cell migration and invasion
[39,41,140]. Thus, in mammals, the Hpo pathway might regulate
cell migration, although this question has not been examined in
detail in flies.
CONCLUDING REMARKS: THE HPO PATHWAY AS A SENSOR OF
EPITHELIAL HEALTH
In summary, numerous studies have highlighted the interplay
between the Hpo pathway and apico–basal cell polarity/cell–cell
contacts. The idea of the Hpo pathway as a sensor of epithelial
architecture/integrity rather than a stereotypical ligand–receptor
signal transduction pathway is emerging. We can speculate that
the Hpo pathway receives various inputs reflecting epithelial
‘health’. Such inputs would include polarity and positional
information encoded by morphogens (are the cell’s neighbours
correctly specified and polarized?), but also mechanical forces or
stress signals. By computing these different inputs, ranging from
information about cell-intrinsic (polarity) to ‘social’ or tissue
properties (morphogen gradients, tension, adhesion), the Hpo
pathway would ensure harmonious growth during development
and participate in maintaining homoeostasis in adult tissues
through the control of regeneration. Just as the past decade has
yielded a detailed understanding of the core Hpo pathway cascade,
the next few years will hopefully see the elucidation of these
regulatory inputs.
ACKNOWLEDGEMENTS
We are grateful to Paulo Ribeiro, Tobias Maile and Pedro Gaspar for critically reading
the manuscript prior to submission. We apologize to colleagues whose work we couldn’t
include because of space restrictions.
FUNDING
Work in the Tapon laboratory is funded by Cancer Research UK.
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