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ScienceDirect Sensing the local environment: actin architecture and Hippo signalling Pedro Gaspar1,2 and Nicolas Tapon1 The Hippo network is a major conserved growth suppressor pathway that participates in organ size control during development and prevents tumour formation during adult homeostasis. Recent evidence has implicated the actin cytoskeleton as a link between tissue architecture and Hippo signalling. In this review, we will consider the evidence and models proposed for the regulation of Hippo signalling by actin dynamics and structure. We cover aspects of signalling regulation by mechanotransduction, cytoskeletal tethering and the spatial reorganization of signalling components. We also examine the physiological and pathological contexts in which these mechanisms are relevant. Addresses 1 Apoptosis and Proliferation Control Laboratory, Cancer Research UK, London Research Institute, 44 Lincoln’s Inn Fields, London WC2A 3LY, UK 2 Instituto Gulbenkian de Cieˆncia, Rua da Quinta Grande 6, Apartado 14, 2780-156 Oeiras, Portugal Corresponding author: Tapon, Nicolas ([email protected], [email protected])

Current Opinion in Cell Biology 2014, 31:74–83 This review comes from a themed issue on Cell cycle, differentiation and disease Edited by Stefano Piccolo and Eduard Batlle

http://dx.doi.org/10.1016/j.ceb.2014.09.003 0955-0674/# 2014 Elsevier Ltd. All right reserved.

Introduction The arrangement and dynamic behaviour of actin filaments supply the protrusive force for cell movement, determine the shape of migrating cells, and provide the cortical tension necessary for maintaining cell/cell and cell/matrix contacts. These functions depend on a complex network of actin filaments that extends throughout the cytoplasm and is controlled by a large array of actin binding proteins (ABPs), including actin nucleators, depolymerising factors, actin-bundling proteins and actin-crosslinking protein [1,2] (Figure 1). Importantly, the F-actin cytoskeleton is a major vehicle for signal transduction, being implicated in the control of numerous signalling pathways, such as the Hippo, Ras-MAPK, PI3K and NF-kB pathways [3,4]. Furthermore, monomeric G-actin is a direct modulator of Current Opinion in Cell Biology 2014, 31:74–83

signal transduction through binding to MAL-MRTF transcription factors [5,6]. Thus, the actin cytoskeleton not only determines cell and tissue architecture but also provides a link between a cell’s mechanical environment and the signalling pathways regulating its behaviour. In this review, we will focus on recent evidence linking actin dynamics and structure to Hippo signalling, a highly conserved signalling pathway that controls tissue growth and cell fate decisions during development and adult homeostasis. The Hippo pathway was discovered in Drosophila genetic screens for inhibitors of tissue growth, and its function as a tumour-suppressor pathway is conserved in vertebrates, where its deregulation is thought to drive tumour formations in a number of contexts [7,8]. The central component of the Hippo pathway is the transcriptional co-activator Yorkie (Yki, or Yes-Activated Protein — YAP and transcriptional co-activator with PDZbinding motif — TAZ in mammals). Yki/YAP/TAZ binds to transcription factor partners (primarily Transcriptional Enhancer Activator Domain — TEAD1-4, or Scalloped in flies), driving a transcriptional programme that specifies cell growth and proliferation, as well as a number of cell fate decisions, depending on cellular context [9]. Yki/YAP/TAZ activity is regulated by a core kinase cascade typically composed of upstream Ste-20-like kinases (Hippo in Drosophila, MST1/2 in mammals), and downstream Ndrlike kinases (Warts in Drosophila, LATS1/2 in mammals), as well as the scaffold proteins Salvador/WW45 and Mats/ Mob1 (Figure 2). Phosphorylation of Yki/YAP/TAZ by Wts/LATS1/2 creates a 14-3-3 binding site, which is thought to restrict nuclear import, and, at least in mammals, causes YAP/TAZ ubiquitin-dependent degradation. In addition to the core kinase cascade, a number of physical tethering mechanisms have ben proposed to retain Yki/ YAP/TAZ in the cytoplasm (see below). Over the last few years, several upstream cues influencing Hippo signalling have been identified, including apicobasal and planar cell polarity, cell-cell contacts, the actin cytoskeleton, and G-protein coupled receptors [9] (Table 1). Since most of these cues relate to tissue architecture, Hippo signalling has been proposed to act as a sensor of the local cellular microenvironment.

Regulation of Hippo signalling by F-actin polymerisation Several early reports implicated Hippo signalling as a sensor of the state of the actin cytoskeleton. In mammalian cells, MST1/2 were shown to associate with actin www.sciencedirect.com

Actin architecture and Hippo signalling Gaspar and Tapon 75

ON

eg. vinculin, zyxin, ajuba

barbed-end polymerization

sequestering

OFF

severing

capping

pointed (-) end

eg. ERM

new barbed-ends

eg. cadherins, nectins, integrins

adhesion complexes

actomyosin contractility

eg. α-catenin, talin

YAP/TAZ/Yki activity

Figure 1

barbed (+) end ADP-actin

ADP(Pi)-actin

ATP-actin G-actin

formin

Capping Protein Ena/VASP

non-muscle myosin II

Actin-Profilin Actin-Cofilin Actin-CAP

cross-linker (eg. a-actinin) mechanosensor (eg. zyxin, vinculin)

Current Opinion in Cell Biology

F-actin structures and regulatory processes relevant to the regulation of Yki/YAP/TAZ activity. Activity of YAZ/TAZ/Yki is correlated in descending level from top to bottom to the presence of actin structures depicted in the schematic. Note that these F-actin structures are often associated with adhesion complexes at the cell surface, represented by various layers of cytoskeleton-interacting proteins. Wriggly lines represent mechanical forces.

stress fibres and to respond to actin drugs such as the polymerisation inhibitor Cytochalasin D by promoting JNK activation [10]. In vivo, the phenotypic analysis of mutations in the Drosophila Capping Protein ab heterodimer (CP), which restricts the growth of actin filament barbed ends, revealed an upregulation of Yki target genes [11,12,13]. Furthermore, a screen for Hippo pathway upstream regulators in Drosophila cell culture suggests that other ABPs controlling F-actin levels, such as Diaphanous (a formin-related actin polymerisation driver) and Cofilin (an actin depolymerisation factor) are also critical to control Yki activity [14]. Recent evidence demonstrates that mammalian CapZ (a capping protein), Cofilin and Gelsolin (an actin severing factor) antagonise YAP/TAZ in mammalian cells [15], while barbed-end F-actin polymerisation promoted by the mammalian Diaphanous formin, promotes YAP nuclear accumulation [16]. Thus, capped or destabilized actin filaments promote sequestration of YAP in the cytoplasm, whereas barbed-end polymerisation favours YAP/Yki activity (Figure 1). However, it is not yet clear whether and how sub-types of actin structures (e.g. stress fibres, lamellae, junctional actin) differ in their ability to promote YAP activity. Important recent work has linked cytoskeletal tension to YAP/TAZ activity [16,17]. Cells placed on hydrogel matrixes or elastic pillars of increasing stiffness, www.sciencedirect.com

corresponding to different tissue environments, respond by increasing YAP nuclear localisation and activity. Furthermore, YAP, which is normally cytoplasmic in cells grown at high density [18,19], can re-enter the nucleus upon stretching in cells grown at high density on an elastic substrate [15]. The elevated YAP activity observed on stiff mechanical environments is dependent on nonmuscle myosin contractility, since inhibition of myosin light chain (MLC) activatory phosphorylation, for example by treatment with ROCK (Rho-associated, coiled-coil containing kinase) inhibitor, abolishes YAP activity on stiff matrix [16,20]. Many lines of evidence suggest that cells placed in a stiff mechanical environment respond by assembling contractile actin networks in order to counteract the forces they are experiencing [21]. Therefore, it has been suggested that the YAP/TAZ can sense and respond to the local mechanical environment by sensing contractile actin networks (Figure 2). However, YAP/TAZ activation induced by cell re-attachment is sensitive to direct Rho inhibition by C3 transferase, but insensitive to myosin II inhibition by blebbistatin. This indicates that, at least in some situations, other Rho signalling targets than myosin II are relevant for YAP/ TAZ responses to mechanical cues. For instance, Diaphanous and Cofilin are also targets of Rho signalling that have a reported effect on YAP/TAZ mechanical responses [15,16,22]. In addition, other GTPases, such as Rac Current Opinion in Cell Biology 2014, 31:74–83

76 Cell cycle, differentiation and disease

Figure 2

LPA, S1P

GPCR

JAMs, Occludins, Claudins

E-CAD

extracellular space

CRB3

P

Gα 12/13

β-Cat γ-Cat

RHO

Eplin

α-Cat

FRMD6

AMOTs AMOTs

KIBRA

YAP/TAZ

Afadin

YAP/TAZ

Rich1

14-3-3

YAP/TAZ

Rich1

P

ATP

P

LIMK

P

mechanosensing /actin polymerization

Cdc42

MST 1/2

P

P

LIMD1 JUB WTIP

Rac

ADP

PP2A

Dia-driven actin polymerization

Pals1

NF2 AMOTs

LATS WW 45 Mob1 1/2

P

α-actinin Vinculin

ROCK

ZO1 ZO2

14-3-3 actin polymerization

F-actin bundles / actomyosin contractility

LATS 1/2

F-actin severing F-actin capping

MYPT1

ZO2

P

YAP/TAZ

YAP/TAZ IKK

YAP/TAZ β-Cat

Vinculin

NF2

YAP/TAZ

target genes

YAP/TAZ TEAD 1-4

TCF/ LEF

P

YAP/TAZ

YAP/TAZ

nucleus

talin

Mammalian

cytosplasm

Integrins

extracellular space

Dachsous

E-Cadherin

Echinoid

Crumbs Fat

β-Cat

γ-Cat

α-Cat mechanosensing

KIBRA

Merlin

Warts

Yki

Cno

Merlin KIBRA

Dachs

Jub

Ex

Mats

Warts

Ex

Sav Sav

P

Yki

P

P

ROCK

Hippo

14-3-3

actomyosin contractility

P

Dachs F-actin capping mechanosensing / actin polyerization

Ena-driven actin polymerization

Zyx

Yki Yki Yki

Yki

Dia-driven actin polymerization

target genes nucleus

Sd cytoplasm

Drosophila Current Opinion in Cell Biology

Simplified schematic representation of cytoskeletal features and mechanisms associated with mammalian (a) and Drosophila (b) Hippo signalling. Note that core inhibitory complexes of Yki/YAP/TAZ are represented in red and activatory transcriptional complexes of Yki/YAP/TAZ are represented in green. Actin cytoskeleton structures are illustrated according to the descriptions shown in Fig. 1. Current Opinion in Cell Biology 2014, 31:74–83

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Table 1 List of actin binding proteins associated with Hippo signalling. For each actin binding protein we list the reported effects on the Hippo kinase cascade and Yki/YAP/TAZ activity. Orthologs are given for mammals and Drosophila Actin binding proteins Mammalian

Function in actin architecture/dynamics Drosophila

Core actin dynamics machinery Capping Capping protein Protein (CAPZA1/CAPZA2/ CAPZA3/CAPZB) (cpa/cpb) Cofilin (CFL1/CL2) Twinstar

Gelsolin (GSN)

Gelsolin

Cyclase associated protein (CAP1/CAP2)

Capulet

Diaphanous-like formins (DIAPH1/DIAPH2/DIAPH3)

Diaphanous

Other actin binding proteins Class II Myosins

Effect on Hpo core kinase phosphorylation

Willin (FRMD6)

Expanded

Neurofibromin 2 (NF2)

Merlin

Ezrin (EZR)



Filamin (FLNA/FLNB/FLNC)

Cheerio

a-Catenin (CTNNA1/CTNNA2/CTNNA3) Zyxin-like proteins (ZYX/LPP)

a-Catenin

Ajuba-like proteins (JUB/LIMD1)

Ajuba

Zonulins (ZO1/ZO2)

Polychaetoid

Angiomotins (AMOT/AMOTL1/AMOTL2)



Zyxin

Capping of F-actin barbed ends and inhibits polymerisation

[15]

Drosophila

Mammalian

Effect on expression of Yki/YAP/TAZ target genes

Drosophila

Mammalian

Drosophila

U [11]

U [15]

U [11]

U [15]

U [11,14]

F-actin severing, ADP-actin monomer sequestration and formation of nonpolymerizing actin rods F-actin severing and capping

?

?

U [15]

?

U [15]

U [14]

?

?

?

?

?

U [15] ?

?

Sequestration of free ADP-actin monomers and promotes F-actin severing by cofilin Barbed-end F-actin polymerisation

U [15] ?

?

?

U [14]

?

U [16]

U [14]

F-actin bundling and contractility

?

?

?



?

U [16] –

?

F-actin tethering to the plasma membrane. Promotes Zyxin association with F-actin F-actin tethering with transmembrane proteins, namely the polarity determinant Crumbs F-actin tethering with transmembrane proteins. Regulation of Rac/Cdc42 F-actin tethering with transmembrane proteins. F-actin antiparallel cross-linking

U [16] –

U [92–94]

U [27,95]

U [92]

U [90,96,97]

U [92,93]

U [27]

U [28,41,98] U [92] ?

U [27,41] –

U [28] ?

U [90] –

U [28,99] ?

U [27] –

?

?

?

?

U [73] ?

?

?

?

U [73,74,101] ?

U [73,101] ?

U [100] ?

U [66]

?

?

U [66]

?

U [66]

?

?

?



U [103] U [26,53,58,104,105]

?

U [26,47,49,53,58]

U [102,103] U [26,47,53,58,104]

F-actin tethering to the Cadherinbcatenin complex Promotes F-actin polymerisation by Enabled/VASP proteins and possibly F-actin cross-linking by a-actinin Possible F-actin tethering to acatenin in adhesion complexes. Regulation of Rac F-actin tethering to tight junction complexes F-actin tethering to tight junction complexes. Regulation of Rac/Cdc42

?

U [90]

U [67]



U [11,14]

U [91]

U [67]



Actin architecture and Hippo signalling Gaspar and Tapon 77

Current Opinion in Cell Biology 2014, 31:74–83



Class II Myosins Dachs

Mammalian

Effect on Yki/YAP/ TAZ subcellular localisation

78 Cell cycle, differentiation and disease

and Cdc42 have been implicated in YAP/TAZ activation [22,23,24]. The involvement of the core kinases in the response to the mechanical environment remains under investigation. It is clear that contact inhibition at high cell density leads to increased YAP phosphorylation [18]. Furthermore, increased actin contractility can promote YAP phosphorylation by LATS1/2 [25], and treatment of cultured cells with actin depolymerising drugs lead to a strong increase in YAP inhibitory phosphorylation [15,17,18]. However, LATS1/2 inhibition or the expression of YAP/TAZ phospho-mutant forms which cannot be phosphorylated and inhibited by LATS1/2 (YAP-S5A or TAZ-S4A) are not sufficient to reactivate YAP in cells plated on a soft mechanical environment [15], though two reports suggest that LATS inhibition or mutation of the LATS sites maintains nuclear YAP in cells treated with Cytochalasin D or Latrunculin B, respectively [17,26]. Interestingly, while mammalian LATS1/2 is not required to modulate YAP responses in a mechanically soft environment, its inhibitory effect on YAP/TAZ can be restored if CapZ levels are decreased and hence the F-actin networks are re-established [15]. The same is true for the activating effect of the GPCR ligand TRAP6 on YAP/TAZ, which is abolished on soft mechanical environments, but restored upon reduction of CapZ levels [15]. Thus, while the activity of the core kinase cassette is sensitive to ‘mechanical information’, its ability to influence YAP/TAZ activity may be overridden by the requirement for a functional cytoskeleton — therefore the cytoskeleton stimulus may dominate the YAP/TAZ response in some contexts (for instance on soft mechanical environments). The cytoskeletal mode of regulation could involve additional post-translational modifications activating YAP/TAZ that can only take place in the presence of a favourable actin cytoskeleton. Alternatively, membrane tethering of YAP/TAZ may be disrupted by Factin, as has been proposed for Amot (see below). The identity of the mechanical sensor mechanism(s) remains an area of intense investigation. In addition to regulators of actin polymerisation such as CapZ and Cofilin, a number of actin-associated factors have been shown to modulate Yki/YAP/TAZ activity. The function of these factors will be discussed in the sections below.

Regulation of Hippo signalling by ERM proteins and angiomotins Expanded (Ex) and Merlin (Mer) were the first upstream Hippo pathway regulators to be identified in Drosophila [27] with a role for Mer later shown in mammals [18,28]. Mer/NF2, which (like Ex) encodes a FERM (Four point one Ezrin Radixin Moesin) domain-containing protein, is mutated in the familial cancer syndrome Neurofibromatosis type-2 [29–31]. Many FERM proteins, including Current Opinion in Cell Biology 2014, 31:74–83

Mer, exhibit a closed ‘head-tail’ molecular conformation, where the C-terminal end associates with the N-terminal FERM domain [32–34]. In sparse cultured cells, Mer is phosphorylated by PAK (p21-activate kinase) on Ser518, promoting a closed inactive conformation [35–38]. Upon reaching confluency, decreased PAK activity and Mer dephosphorylation by the MYPT/PP1 complex [39,40] leads to opening of Mer and activation of its growth inhibitory function. Thus, Mer is a mediator of contact inhibition of growth and a key sensor of cellular crowding. Mer is thought to modulate Hippo signalling through several distinct modes of action. Firstly, Drosophila Mer directly binds to and recruits Wts to the apical plasma membrane, where it can be activated by the upstream kinase Hpo [41]. Secondly, active mammalian Mer translocates to the nucleus where it binds to and inhibits the CRL4DCAF1 E3 ubiquitin ligase [42]. CRL4DCAF1 ubiquitylates LATS1 and LATS2, leading to their degradation or inhibition [43]. It is unclear whether these modes of regulation operate in parallel in both species, or if they represent divergent upstream regulation modes for the Hippo core kinase cassette between neodipterans and mammals [44]. Finally, in mammalian cells, Mer associates with the Angiomotins (Amot, Amot-like 1/2–AmotL1/2), which have been proposed to inhibit YAP/TAZ activity. The Amot proteins were identified as prominent YAP/ TAZ-binding proteins in Affinity Purification/Mass Spectrometry experiments [45,46]. They reduce YAP/TAZ activity, both by directly tethering it to the plasma membrane via a WW domain/PPxY interaction [45–47], by recruiting the AIP4/Itch ubiquitin ligase to induce YAP/ TAZ degradation [48] and by recruiting LATS2 to promote YAP/TAZ inhibitory phosphorylation [49,50]. Amot, along with Mer, is part of a polarity complex located at the tight junctions of mammalian epithelial cells, comprising the trans-membrane polarity protein Crb3 (Crumbs 3) and the PDZ domain proteins Pals1 and Patj [51,52]. Depletion of Crb3 or Pals1 leads to a persistence of nuclear YAP/TAZ in confluent epithelial cells, suggesting that the Crb3/Mer/Amot complex is required for contact-mediated YAP/TAZ sequestration [19]. Surprisingly, Amot has also been reported to function as a YAP/TAZ co-factor in the nucleus, hinting at a dual role as an activator and inhibitor [53]. The unrelated FERM domain protein Ex appears to fulfil an analogous function to Amot in diptera, with the FERM domain mediating binding to Drosophila Crb [54], and three PPxY motifs binding the Yki WW domains, thereby mediating Yki cytoplasmic retention independently of the core kinase cassette [55,56].

Links between actin and Yki/YAP/TAZ regulation through Mer and Amot Both Mer and Amot have been reported to affect actin assembly and Hippo signalling, begging the question of whether these outputs are related. However, it is unclear www.sciencedirect.com

Actin architecture and Hippo signalling Gaspar and Tapon 79

whether the ability of Mer/Amot to modulate Rac/Rho activity is relevant to YAP/TAZ regulation. Indeed, a structure/function analysis of Mer suggests that its actin polymerisation and growth control functions are separable [57]. Several lines of evidence suggest that the status of the actin cytoskeleton affect Yki/YAP/TAZ activity via Mer and Amot (Figure 2). Firstly, loss of cytoskeletal integrity, such as upon latrunculin B treatment, promotes Mer/Wts interaction and therefore Wts activation [41]. Secondly, Amot proteins are required for YAP/TAZ cytoplasmic retention upon actin depolymerising drug treatment [58]. Mutation of Amot’s F-actin binding motif increases its ability to retain YAP/TAZ in the cytosol, and F-actin competes with YAP/TAZ for binding to Amot [58]. Thus, Amot may function as a sensor of polymerised actin whose ability to inhibit YAP/TAZ by direct binding is blocked by sequestration through F-actin binding. Indeed, recent evidence has shown that Amot depletion restores YAP/TAZ activity after Latrunculin A treatment, while LATS1/2 depletion does not [22]. Interestingly, Amot is phosphorylated by LATS1/2 at Serine 175 in its actin-binding motif, resulting in reduced F-actin association [46,50,58,59]. Since phosphomimicking forms of Amot display an increased ability to inhibit YAP/TAZ, this provides a link between the activity of the Hippo core kinase cascade and actin-dependent YAP/TAZ activity.

LIM domain proteins in Hippo signalling The vertebrate Zyx family can be split into two branches based on similarity between their conserved C-terminal LIM-domains (Lin11, Isl-1 and Mec-3, a form of Zinc finger): the Zyx branch including Zyx, LPP and Trip6 and the Ajuba branch, including Ajuba, LIMD1 and WTIP [60]. Members of the Zyx branch have been implicated in actin regulation. Vertebrate Zyx and LPP recruit the actin binding proteins Enabled (Ena) and VASP (Vasodilatorstimulated phosphoprotein) to focal adhesions and cellcell contacts, where they promote F-actin polymerisation [61–65]. In Drosophila, the only members of the Zyx protein family, Zyx and Jub, are required for normal tissue growth and both promote Yki activity through distinct mechanisms [66,67,68]. Drosophila Zyx has been proposed to bind the atypical myosin Dachs to promote Wts degradation via an unknown mechanism [67]. Drosophila Jub and mammalian Ajuba/LIMD1 binds to Wts/LATS1/2 and is thought to inhibit its ability to phosphorylate Yki/YAP/TAZ [66]. Several studies suggest that LIM domain proteins are attractive mechanosensitive Yki/YAP/TAZ regulators (Figure 2). For instance, Zyx, which is normally localised at focal adhesions and cell junctions in cultured www.sciencedirect.com

mammalian cells and Drosophila follicular epithelial cells, is recruited to F-actin sites where new barbedends have been exposed, through severing or damage of actin fibres by mechanical strain or laser ablation [65,69,70]. However, whether Zyx relocalization to strained or severed actin fibres is relevant for mechanosensitive Hippo signalling remains unexplored. Two recent reports have examined the role of Jub in mechanical regulation of the Hippo pathway [68,71]. ROCK depletion in the developing fly wing leads to reduced cytoskeletal tension and Yki-dependent tissue growth, while ROCK or activated MLC overexpression increases tension and growth. Increased tension upon ROCK/activated MLC expression drives increased apical recruitment of Jub and Wts to junctional punctae and association with the adherens junction (AJ) component a-catenin [68]. Furthermore, in mammalian cells, JUB associates with LATS kinases upon cyclic stretch and this is dependent on the activity of the JNK (c-Jun N-terminal kinase) pathway [71]. This suggests that cytoskeletal tension influences Yki activity by promoting Wts recruitment into a junctional inhibitory complex with Jub. a-catenin has been reported to undergo a force-dependent change in conformation [72] and may therefore act as a direct tension sensor, recruiting Jub and Wts when a certain junctional tension threshold is reached. Interestingly, in mammalian keratinocytes, a-catenin is thought to promote YAP tethering by interacting with 14-3-3 proteins without affecting the activity of the core kinase cascade [73]. However, the mechanisms for a cell-cell junction mode of Yki/YAP/TAZ regulation may be cell-type specific. For instance, another study showed that E-cadherin engagement promotes YAP inhibition by the core kinase cascade in MCF10A mammary epithelial cells [74]. It is also important to note the distinction between mechanisms that involve force transmission through cell-cell junctions from those that involve the cell-extracellular matrix interface (as is the case in hydrogel and elastic pillar experiments discussed in the first part of this review), as these rely on different molecular components.

Regulation of the actin cytoskeleton by the Hippo pathway As well as being regulated by the actin cytoskeleton, the Hippo pathway in turn appears to influence actin assembly. For example, mutations in ex, hpo and wts lead to apical F-actin accumulation in Drosophila imaginal discs [11,12,13]. Furthermore, phosphorylation of Ena by Wts is required for proper migration of the border cell cluster in Drosophila ovaries [75]. Interestingly, cytoskeletal regulation seems to be a conserved feature of NDRfamily kinases. Thus, the core kinase cascade may have evolved to restrict Yki/YAP/TAZ activity both by direct phosphorylation and by antagonising the formation of pro-Yki/YAP/TAZ F-actin structures. Current Opinion in Cell Biology 2014, 31:74–83

80 Cell cycle, differentiation and disease

Concluding remarks Yki/YAP/TAZ are strongly influenced by actin architecture and mechanical cues, thus acting as cellular sensors of the physical environment. A number of possible physiological and pathological contexts for this mode of regulation have recently emerged. How final organ size is achieved during development remains one of the most elusive questions in biology. Several theoretical studies of the Drosophila wing have proposed the idea that the gradual altering of stress patterns as the tissue grows might provide a ‘developmental clock’ that drives timely growth arrest once a physical force gradient through the tissue has reached a certain threshold [76,77,78]. Indeed, the patterns of tissue stress in the wing are spatially and temporally modulated [68,79–81]. Given the known role of Hippo signalling as a ‘cell crowding’ sensor in cell culture [15,18] and the recent suggestion that Yki activity is modulated by tissue contractility during fly wing development [68], the Hippo pathway is an attractive candidate to mediate such an effect. An understanding of the relative contributions of possible mechanotransduction mechanisms and a clear demonstration that Yki/YAP/TAZ activity follows endogenous patterns of tissue stress during fly and mammalian organ development are likely to emerge over the next few years. In addition to tissue growth, Hippo signalling is involved in controlling a number of cell fate choices and morphogenetic events. It is increasingly evident that, like growth control, cell fate specification is dependent not only on chemical signals such as morphogens but also on specific information provided by the physical characteristics of the local microenvironment. For instance, YAP/TAZ are required for rigidity-dependent osteogenic versus adipocyte differentiation of mesenchymal stem cells [16] and motor neuron differentiation in human pluripotent stem cells [82]. In rigid culture conditions, YAP/TAZ is activated, promoting osteogenic differentiation, but silencing YAP/TAZ favours the adipocyte fate regardless of the mechanical environment [16]. Interestingly, YAP/TAZ is required for the cells to retain a memory of their past mechanical exposure [83]. In the developing mouse kidney, the actin regulator Cdc42 promotes the activation of a YAP/TAZ-dependent nephron morphogenetic transcriptional programme [24]. Finally, the actin-associated proteins Mer and Amot are key to the YAP/TAZ-dependent specification of trophectoderm versus inner cell mass in the pre-implantation mouse embryo [50,84,85]. Thus, actin-dependent/mechanical regulation of Hippo signalling appears to be a widespread phenomenon during development, and has also been implicated in several pathological situations. First, Yki/YAP/TAZ activation is required for the repair of injured epithelial tissues in flies and mice [86] and this may involve Current Opinion in Cell Biology 2014, 31:74–83

JNK-dependent phosphorylation and activation of Jub [68]. Second, MST1 has been implicated in the response to pressure overload in the heart [87]. Finally, the relative stiffness of the tumour microenvironment is thought to participate in tumour growth and dissemination [88]. For instance, tumour cells can promote YAP/ TAZ-dependent activation of carcinoma-associated fibroblasts (CAFs), leading to extracellular remodelling and further tension-dependent YAP/TAZ activation [20]. Furthermore, the role of the cytoskeleton in promoting YAP/TAZ activity in a tumour context is supported by recent genetic evidence: gain-of-function mutations in subunits of the heterotrimeric G-protein Gaq lead to YAP/TAZ activation via Rho signalling in uveal melanomas [22,89]. In this context, YAP/TAZ activation is proposed to occur via reduced inhibitory phosphorylation [89] and via Rho/Rac-mediated actin polymerisation disrupting the Amot/YAP inhibitory complex [22]. It is therefore to be hoped that the study of mechanical/ actin-dependent signalling will not only answer longstanding developmental questions, but will also impact on treatment of several human diseases.

Acknowledgements Pedro Gaspar was supported by the Fundac¸a˜o para a Cieˆncia e a Tecnologia (Portugal). Work in the Tapon lab is supported by Cancer Research UK. We apologise to colleagues whose work we could not cite because of space constraints.

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41. Yin F, Yu J, Zheng Y, Chen Q, Zhang N, Pan D: Spatial  organization of Hippo signaling at the plasma membrane mediated by the tumor suppressor Merlin/NF2. Cell 2013, 154:1342-1355.

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42. Li W, You L, Cooper J, Schiavon G, Pepe-Caprio A, Zhou L, Ishii R,  Giovannini M, Hanemann CO, Long SB et al.: Merlin/NF2 suppresses tumorigenesis by inhibiting the E3 ubiquitin ligase CRL4(DCAF1) in the nucleus. Cell 2010, 140:477-490.

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Current Opinion in Cell Biology 2014, 31:74–83

Sensing the local environment: actin architecture and Hippo signalling.

The Hippo network is a major conserved growth suppressor pathway that participates in organ size control during development and prevents tumour format...
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