E-Cadherin–Integrin Crosstalk in Cancer Invasion and Metastasis

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Cancer Margaret Edinburgh Serrels, Alan Canel, Marta and invasion metastasis cancer in crosstalk E-cadherin–integrin Commentary eitdb nernma are integrin that by interactions mediated cell–ECM and E-cadherin between metasta E-cadherin interplay and the of invasion role cell the tumour review in we Here, interactions. cell–ECM and enviro tumour surrounding the from T invasion. co and cell–cell migration collective of loosening a that and Behrens, adhe t and cell–cell that functional and (Birchmeier clear intact is tumours it epithelial However, 1994). many in can behaviour E-cadherin stromal of loss and and tumour o tissues, mediator adjacent key with a is and E-cadherin cells. ECM surrounding the the ch with of to ability nature their is evolving metastasise to the and that trait behaviour One microenvironment. cell of cancer multiplicity of plasticity the by inhibitin complicated Weinberg, and and (Hanahan understanding cancer 2011), of In ‘hallmarks’ macro-metastases. other into with development common their resu haematogenous and or lesions the metastatic lymphatic and the through systems, is cells migratio tumour spread malignant local metastatic including comp as steps, a is metastasis research, and invasion cancer and for in invade responsible cells challenges tumour (an great sites which distant by to metastasise processes the Understanding Introduction ( words: Zaidel-Bar al. Key ( Ronen et by Rooij adhesion McCormack glance’ de a focal Jessica at cross- Johan by adhesome Src, and ‘Cadherin regulators’ the kinases Huveneers articles: GTPase related Stephan GTPases. adhesion-linked Rho see control by please with the of reading, interface’ adhesion cells further of family cadherin–F-actin For cell–cell role Adhesion. Rho the around tumour on the ‘Cycling the Minifocus govern a which 378). discuss and of which part will (ILK), by is article we contacts, kinase This mechanisms particular, integrin-linked cell–matrix In the and integrin-mediated tumours. (FAK) review and of that kinase microenvironment potential we adhesions tumour metastatic the cell–cell Here, from and often cues E-cadherin-mediated invasion. invasive external is dynamic to extracellular and respond surrounding between coordinated progression cells migration the the as regulation requires dynamic Tumour contact directional This is that adhesion phenotype. polarity, interactions. adhesions of invasive types and regulate integrin-mediated cell–cell both motile and of more homophilic adhesions Regulation a (ECM). to cell–cell mediates matrix transition E-cadherin-mediated the that both and function of protein E-cadherin regulation of transmembrane loss the single-pass with associated a is E-cadherin Summary 10.1242/jcs.100115 doi: 393–401 126, ß Science Cell of Journal ( correspondence for *Author 03 ulse yTeCmayo ilgssLtd Biologists of Company The by Published 2013. -ahrn nern,Cne,Invasion Cancer, Integrins, E-cadherin, , 0 fcne-eae otlt.Tmu cell Tumour mortality. cancer-related of 90% [email protected] rxrcpos ediscu We receptors. trix tn rwho ooiaino micro- of colonization or growth lting o otre hm,i n fthe of one is them), target to how d n nain ismnto of dissemination invasion, and n nepn h blt fcne cells cancer of ability the underpins netewyi hc hyinteract they which in way the ange mu el a naewt fully with invade can cells umour e rcs htivle multiple involves that process lex in scletv ruso cells, of groups collective as sions tcsi ufcett emtthis permit to sufficient is ntacts rmt naieadmetastatic and invasive promote enitgi-adE-cadherin- and integrin- ween elcl dein nepithelial in adhesions cell–cell f i eurscodnto fcues of coordination requires his mn,t euaebt cell–cell both regulate to nment, i,wt atclrepai on emphasis particular with sis, nainadmtsai are metastasis and invasion g neligmcaim,the mechanisms, underlying ) stekysignalling key the ss .Cl Sci. Cell J. 126 eitdahsos hc oen -ahrnahsv strength adhesive E-cadherin migration. cell governs and which adhesions, mediated hc c oln h ut-rti ope oteactin the to complex multi-protein the the link through of to cytoskeleton members namely act to family, which binds The protein 2008). E-cadherin Berx, catenin of and Roy domain on van molecules cytoplasmic by (reviewed opposing cells with neighbouring interaction homophilic dependent otiigfv xrclua eet htmdaeisCa its of mediate that development repeats the extracellular generate for five cannot containing required embryos 1995). al., et is Riethmacher the 1994; al., et as which (Larue the organisms multicellular in lethal, epithelium, E-cadherin embryonic encoding al., an et gene is Hyafil the 1981; of in mouse al., knockout adhesion et Targeted cell–cell (Hyafil 1980). blastomeres mediated embryo that mouse protein early surface cell dependent ahrn n sfuda deesjntos(J) tutrsthat structures (AJs), junctions interactions adherens cell–cell at m found mediate is prototypical and the cadherins is E-cadherin junctions adherens and E-cadherin hrl fe h ytei fEcdei n cst chauffeur to acts and of E-cadherin of binding synthesis The the 2012). after cytoskeleton shortly Yap, actin their close the and of a and indicating disruption (Ratheesh dynamics integrity, junction junctional and of between (WASP) AJs, loss interplay a to protein to localised leads actin function syndrome are dynamic members Wiskott-Aldrich the family 1). complex, on (Fig. and Arp2/3 the dependent assembly localised as Ena/VASP such also AJs regulators, to actin is for Many leads cytoskeleton. AJs required then of is cells Maintenance that adjacent remodelling on actin complexes catenin 403-413). , -ahrni igeps rnmmrn glycoprotein transmembrane single-pass a is E-cadherin .Cl Sci. Cell J. 126 a 7-9) Mcaoestv ytm tthe at systems ‘Mechanosensitive 379-391). , ctnn h lseigo cadherin– of clustering the -catenin; twsfrtdsoee saCa a as discovered first was It . emberofthetype-1classical b ctnnadp120-catenin, and -catenin b ( .Cl Sci. Cell J. ctnnoccurs -catenin 126 393 373- , 2+ 2+ - - Journal of Cell Science -ahrncae ed aesonta h nta accumulation initial the that shown have of of beads trapping sites laser E-cadherin-coated utilising at experiments E-cadherin Indeed, of adhesion. presence cell–cell the E- (de controlling mechanism circumstances only for for the responsible some not mechanism is endocytosis in However, 2009). major membrane al., et Beco a the at is in exchange endocytosis and cadherin AJs, that at E-cadherin suggested of fact, turnover for dynamic requirement the the in highlighted endocytosis in has study cells FRAP of a instance, monolayers For confluent move. molecules these the which and at pool, rate a within molecules mobile used of proportion been the analyse have recoveryto photoactivation Fluorescence and time. 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E-cadherin levels both cellular of steady-state the controls and membrane plasma and the at contacts, stability cell–cell local of a that supports remodelling membrane structures the from dynamic and to highly molecules E-cadherin of are transport bidirectional rather The remodelling. constant but and rapid undergo static, not are trafficking AJs and dynamics membrane E-cadherin 2006). cadherin– Yap, the and to (Scott modulators complex actin catenin other of actin-filament recruitment of regulation and the dynamics of involves role and the complex, cytoskeleton. that more suggest is actin to catenin the emerged has and evidence recently complex However, the cadherin–catenin through the levels between years, surface many is For cell 2003). 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E- Journal of Cell Science acr(ulode l,19) ngnrl hs uain are the mutations these in general, result In gastric to 1998). familial al., reported to et are generations (Guilford family and cancer several identified of been predisposition E-cadherin and in Berx also mutations GEMIN2) by germline have However, as (reviewed 2009). promoter known Roy, E-cadherin van (also and the SIP1 target which SNAI2), Zeb1, as SLUG SNAI1), known as known (also (also SNAIL repressors transcriptional xrclua niomn oteatnctseeo (Hynes, cytoskeleton actin the to the from cues environment linking thereby extracellular serve interactions, that cell–ECM mediate glycoproteins to cell-surface heterodimeric are Integrins adhesions Integrin-mediated cell–matrix integrin-mediated that between balance factor and the contacts. key and AJs of The status its E-cadherin-mediated and the 2). migration is (Fig. invasive mechanism of 2009) terms underlying in outcome al., net the al., signals et determines et and (Gaggioli Giampieri environment with tumour be 2007; local interactions can the these to from, use; receive according they they adapted invasion and and characteristics particular migration can altered morphological of by cancers modes to advanced employed the respect and Instead, is with definite. plasticity that rarely display cells, is of types tumour groups collective as of and strands (Friedl manner or directional sheets and 2009). polarised of Gilmour, a movement in cells the 2006). epithelial involves Rajasekaran, typically and duringThis (Christiansen example for development morphogenesis, normal embryonic during utilised adhesions collective cell–cell is of facilitate and This maintenance the to 2006). requires or cells sufficient Rajasekaran, of transition movement be and partial and might (Christiansen intact a contacts invasion fully cell–cell that with of and occur loosening adhesions, can invasion cell–cell cell functional also tumour is that it tumour, primary clear the from undergo dissemination can Thiery, facilitate cells to cancer by EMT that signalling (reviewed accepted widely EMT similar is cancer it by Although control 2002). regulated that be those to to and networks appears development and organ repair, required embryogenesis, wound a is is including but EMT processes cells, Indeed, cancer behaviour. for to cell unique normal is that of process manifestation al., a et not is Guarino EMT 2006; 2007). Rajasekaran, and Christiansen cells tumour by of more (reviewed spread metastatic the a a in as event de- with regarded important of is potentially and together patterns, coordinated expression acquisition phenotype, gene in the changes mesenchymal and respective invasive is contacts and EMT cell–cell migratory process 2009). of (EMT) Weinberg, stabilisation transition crucial and epithelial–mesenchymal a as the (Kalluri regarded been in has step adhesion al., cell–cell et of weakening, Perl highly 2006; al., into et cells (Derksen tumour cells 1998). epithelial invasive and of a largely migratory conversion metastasis, is and function the invasion of E-cadherin through promotion of the in loss factor Van that causal breast and demonstrated and pancreatic have (Berx of models cancer (CDH1) animal using of gene Studies loss 2001). E-cadherin heterozygous Roy, human the with wild-type combined found the cancer are mutations breast somatic domain lobular addition, in calcium-binding In identified. E-cadherin, the been of in also form has mutation truncated additional a an of although synthesis the with associated h oso -ahrnadtersligsprsin or suppression, resulting the and E-cadherin of loss The h oeo nain hte ssnl eecya el or cells mesenchymal single as whether invasion, of mode The hs r opie fsrcua,aatradsignalling and adaptor structural, of cytoskeleton. multi- actin comprised of the assembly to are the the integrins through from link These cell that signals the complexes of transmit protein inside Integrins the substrates 2006). different to extracellular outside al., 20 to et binding than biological (Humphries of selective more range a through control to processes differentially to rise act which two gives integrins, combinations of possible consist proteins a membrane-spanning termed subunits, These 2002). nainta el rmasnl uorcnaot F,got factors. growth GFs, adopt. of can modes tumour different single the a govern from that cells invasive E-cadherin that the in invasion a at changes not cues the is environmental control periphery Localised front cell invasion. the cell from for E-cadherin, E-cadherin prerequisite internalised of or loss arrows downregulated that white have demonstrating the that have whereas cells that periphery, individual cells the indicate of at invasion staining E- collective E-cadherin for the retained stained show tumour arrows mammary Yellow mouse cadherin. al., oncogene-induced et (MT) (Canel T B) middle cells in in arrow dynamics (yellow ( E-cadherin E-cadherin 2010b). in membranous changes strong subtle have more that through yellow or (dashed B), periphery through cell in achieved the arrow be at expression can E-cadherin This of junctions movement. downregulation cell permit of to loosening and sufficient with generation being adhesions, the cell–cell requires dynamic also of invasion to maintenance adhesion collective integrin-mediated whereas on ECM, dependent Alexander, are the and invasion (Friedl of structures types adhesive Both microenvironment 2011). between tumour interplay surrounding dependent the the is control this from that and Cancer inputs migration, together. signalling of moving diverse mode cells chosen on of the groups in collective plasticity display as cells or invasion. cells single cell as cancer occur of Plasticity 2. 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Gonfloni, and and and Src Superti-Furga 2010; of activation al., catalytic regulation et full its on and reviews FAK of (for tyrosine loop of kinase autophosphorylation phosphorylation the the in Src-mediated residues to to leading Src FAK, of of binding site For the activity. the permits kinase auto-inhibitory this unclear, increased of FAK, in remain release result FAK that the conformations and requires cell protein kinases Src the both of at of activation activation activation through to integrin from lead mechanisms originate surface precise that the signals signals and which of Although Mitra transmission 2010; 2006). al., the et Schlaepfer, in (Cabodi activation functions integrin key of downstream have FAK and Src FAK and Src tumour the of influences potential crosstalk metastatic cells. and and this ILK invasion how FAK, migration, highlight collective and Src and signals kinases GTPases, tyrosine small links non-receptor the E- the on that data of of recent role evidence regulation discuss we the of Here, to adhesions. cadherin-mediated body adhesions integrin–ECM considerable of downstream a cell–ECM is There crosstalk regulating integrin-mediated intermediates Signalling and 2010). al., et between (Borghi crosstalk adhesions interactions the in role pivotal a that E-cadherin has suggests and migration, this cell defined, and be to yet a are mechanisms molecular ctnni nipratrgltro ohEcdei adhesion E-cadherin both of regulator important an is -catenin h oeo r n A ncnrligAsi complex, is AJs controlling in FAK and Src of role The b ctnnb A eut nals fA nert following integrity AJ of loss a in results FAK by -catenin a ctnn a -catenin; 06.Atog h neligmcaim r o well of not expression control are can Src al., mechanisms that E- et reports underlying of Coluccia are stability 2008; there the al., understood, the Although et controlling (Cicchini by 2006). levels AJs protein regulate cadherin also and can Galliher FAK and 2001; invasive 2009). al., Schiemann, more TGF and a et Wendt with to 2006; (Bhowmick Schiemann, activation linked been phenotype integrin has metastatic coupling which in EMT, induced involved also is is AJs transforming regulates factor control pathway growth that FAK–Src inputs the FAK that signal observation of multiple the role assimilating to integral in factors an Src for growth and support only from Further also not integrity. but AJ originate integrins regulate that through ECM a signals the have coordinating from could or in and junctions, of activation function of phosphorylation pivotal disruption integrin to the lead either and components also by AJ might Src FAK stimulation which transient factor and/or in a growth Src tumours, However, high. in of constitutively and AJs activation is of link, activity disruption FAK cadherin–cytoskeletal a the and/or of in the in resulting affinity of result partners, might the severing binding their or alters for weakening phosphorylation AJs the Tyrosine of components 2012). al., et ope,wihi eurdfrfl ciaino FAK of small activation that or found FAK, full FAK–Src Src-dependent of we depletion recently, a for (siRNA)-mediated require More of RNA 2004). required interference to formation al., is integrin et the E-cadherin shown (Avizienyte on which and of was FAK depend complex, resulting control AJs of to the phosphorylation Furthermore, the of shown 2002). al., of was disruption et (Avizienyte Src regulation signalling by subtle However, internalisation 2005). more al., Early et Palacios endocytosis cells. 2002; a the al., tumour control et (Fujita could of E-cadherin impacts Src of capacity turn oncogenic in that invasive which showed Src and AJs, studies membrane, migratory of cell strength the the the on control at can E-cadherin FAK of and turnover of fine-tuning endocytosis dynamic By the localisation. the regulate membrane its also thereby can and FAK E-cadherin and Src cell, phenotype. the within epithelial an to conversion the assembly and the with AJs associated This of is 2011). expression E- al., E-cadherin the et in of (Li increase regulation SNAIL1 the repressor mouse to transcriptional attributed FAK-null cadherin was in which observed cells, E-cadherin been increased embryonic has an the recently, E-cadherin addition, of In of expression 2001). al., control et (Menke transcriptional promoter through E-cadherin ahas uha ioe ciae rti iae(MAPK), kinase signalling protein kinase activated other mitogen with as invasive cooperate such can and pathways, Src motile AJs? a regulate of acquisition the for phenotype. required not a both have is cells, tumour al., can epithelial of axis et vitro behaviour the integrin–Src–FAK (Canel on the impact membrane E- major by of control cell fine dynamics the the that cadherin show studies at pharmacological these Importantly, E-cadherin 2010b). of whereas movement of collective 2010b), turnover the decreases collective cells Src al., tumour reduced or FAK et and of inhibition adhesions (Canel cell–cell a invasion with of associated is and strengthening endocytosis E-cadherin inhibits integrin, swl sdrc hshrlto fA opnns r and Src components, AJ of phosphorylation direct as well As nadto orgltn h bouelvl fE-cadherin of levels absolute the regulating to addition In owa r h inl ontemo r n A that FAK and Src of downstream signals the are what So and nvivo in b nvivo in (TGF n httecmlt oso elcl junctions cell–cell of loss complete the that and , -ahrnitgi rstl 397 crosstalk E-cadherin–integrin b hc orltswt hne nthe in changes with correlates which , -nue M Cchn ta. 08 and 2008) al., et (Cicchini EMT )-induced b b 1- in - Journal of Cell Science oyo vdneipiaigteesalGPssi the al., of in overview et an provide Lozano GTPases we Here, by small 2012). (reviewed Giehl, and these adhesions Menke 2003; cell–cell implicating substantial of evidence a regulation also is of and there cytoskeleton 2000), body actin (Ridley, are the migration RhoA regulating cell in and directed role Rac1 their CDC42, for known GTPases, best Rho small the Although GTPases in Small overexpressed invasive more is a it phenotype. and tumour when EMT, of aggressive lost induction and AJ be the might in could of ILK resulting behaviour, control tumours, epithelial stages 2003). normal fine al., early control this to et the but rheostat Vespa a in as 2005; act function al., therefore E-cadherin a et (Vespa has and cell–cell formation it at assembly found where been and matrix also adhesions, factors has central ILK both growth keratinocytes, a In control from at expression. signals it that places The the 2001). integrins adhesions coordinating al., integrin et for Tan at position 2008; ILK al., the of et by McPhee localisation 2012; mediated al., be repressors et transcriptional can E-cadherin (Matsui this of families 2004); key ZEB al., and the SNAIL E-cadherin et of be Oloumi expression the by to the (reviewed regulates thought in The ILK is 2004). which by al., involved transcription mechanism et of E-cadherin (Oloumi is induction phenotype of invasive ILK inhibition an more and a of and expression, evidence EMT overexpression E-cadherin of body of that considerable downregulation integrin- a al., suggest also et connects Legate is to by there and (reviewed However, changes 2006). integrins, actin to responses of the mediated with downstream interacts that signalling kinase of protein domains serine/threonine cytoplasmic a is ILK ILK can axis integrin–Src–FAK of been translocation the nuclear of the has to activation lead Here, that 2006). axis al., integrin–Src–FAK pathway et Wnt– the Another the of downstream is 2004). acting in al., implicated upstream for et adhesions of E-cadherin-mediated convergence regulation and of (Avizienyte integrin point the the regulate a that as Therefore, and signals act 2004). can phospho-myosin mediated force al., peripheral contractile E-cadherin et of of (Avizienyte activity formation adhesions the mesenchymal cell–cell a inhibit of maintain accumulation and to peripheral phenotype required the is promote which to phospho-myosin, ROCK, and MLCK 398 ftoeclsta aertie elcl ucin,adthat and junctions, manner. cell–cell collective retained a activities in have invade kinase that and migrate also the pro-invasive cells but FAK only EMT, those undergone a not have of inhibit and that with cells to tumour approach of Src cells dissemination promising a two the provide provides these therefore between can Targeting crosstalk a and advantage. of heart types the and adhesion at Src them E- by places signals both adhesions FAK of varied integrin-mediated control receive and the cells cadherin-mediated microenvironment, surrounding because undoubtedly the context are from and the understood, on fully yet dependent is not are that axis Src–FAK 2006) al., transcriptional et 2009). its al., tumours Koenig aggressive of et and (Schmalhofer 2006; invasive activation more al., with associated subsequent commonly et the (Coluccia and activity AJs, of lhuh h ehnssadsgaln vnsivligthe involving events signalling and mechanisms the Although, ora fCl cec 2 (2) 126 Science Cell of Journal b ctnnptwy(oucae l,20;Koenig 2006; al., et (Coluccia pathway -catenin b itgi uuis thsbe ikdto linked been has It subunits. -integrin b ctnnfloigdisruption following -catenin ecuilfrtedssebyo J,adteaqiiino a of acquisition 2008). the al., et and (Shen AJs, phenotype migratory of more disassembly and to to the mesenchymal reported for been shown on has crucial effect CDC42 been be direct instance, a For also involve cytoskeleton. not actin do have the that mechanisms GTPases by AJs Rho regulate 2002). small ROCK-mediated Marshall, and Interestingly, whereas (Sahai AJs AJs, disrupts contractility actomyosin stabilises downstream mDia-dependent AJs: polymerisation two on effects identified actin opposing with have RhoA Marshall of For effectors substrate. and cell The even Sahai or integrity. type example, cell junction members, expression family levels, of particular activity of on disruption depend leading might or pathway AJs, predominant signalling stabilisation regulate are multiple can either that Rho clear and contacts to Rac is of it Once downstream However, the pathways 1997). 1999; regulates al., al., 2002). Rac et et and (Braga Braga al., adhesions Rho of cadherin-mediated of of proximity et action stabilization the concerted cell–cell (Ehrlich the in initial established, molecules this cells facilitate E-cadherin adjacent can placing Rac1, formation, by lamellipodium by contact the the triggered that been is and is compelling assembly, has E-cadherins which AJ It of the in regulation. interaction step to AJ homophilic first contributed to the GTPases that have Rho suggested that links studies that evidence the of some nti td,Ca study, this In naieadmtsai hntp,i scerta osof loss that more clear a is of it acquisition phenotype, the and metastatic EMT the and with implicates evidence invasive E-cadherin and the regulation of of of most loss Although mode vital. its are understand phenotypes function to cancer in efforts player continuing crucial a that undoubtedly such is is it progression however tumour complex; in are E-cadherin of function which the The perspectives cytoskeleton, and orchestrate invasion. Conclusions actin and migration and cell the directional control interactions, in to through essential coordinate either cell–ECM changes to cues, act extracellular subsequent or GTPases by GTPases small triggered small cell–cell are Thus, other that 2002). of signals al., activity et the (Arthur modulates two also these adhesion between interface 2005). focal al., key et co-workers integrin-mediated a (Balzac and types of at adhesion formation Rap1 Balzac placing the 2006). adhesions with which al., disassembly, associated AJ upon et Rap1 was of is activation Retta strong GTPases a crucial 2005; observed also small Bos, is of and see activation subfamily integrin Ras both of for control the the of 2005). in al., involved member et a (Balzac can adhesions AJs Rap1, whereby integrin-mediated crosstalk, regulate this also of highlighted has bi-directionality evidence potential recent the contacts However, cell–cell adhesions. of integrin regulation the by on focused have cadherins and migration 2007). cell small al., control et other families, (Ramsay to with Rab invasion trafficking and and cooperate membrane (Arf) factor regulate GTPases ribosylation which Rho ADP the that of it and GTPases likely 2001), to Hotchin, very reported and (Akhtar been is Rac1 also of has activation upon E-cadherin occur of endocytosis by cell–cell of contacts disruption the in Moreover, resulting phosphorylation. Src, E-cadherin growth of epidermal stimulation the (EGFR)-dependent triggers receptor turn factor in which activation, CDC42 to ial,i swrhmninn htcadherin-mediated that mentioning worth is it Finally, integrins between interplay the exploring studies most far, So enovo de 2+ omto n eoeln fAs(o reviews, (for AJs of remodelling and formation elto o nywaesAsbtas leads also but AJs weakens only not depletion Journal of Cell Science hto ihydnmcpoes nwihteitrlybetween interplay at the which in outgrowth process, dynamic ultimate highly a of the shot to often cues environmental and evolving sites. invasion local metastatic to local and mechanisms adapt allow cell to tumour progression. ability of tumour their multiplicity for the prerequisite highlights a This always not is E-cadherin nesadn ftecneune fEcdei oson loss E-cadherin complete more of a consequences and 2008), the growth al., affect of also et can understanding (Jeanes E-cadherin of signalling Loss factor 2008). al., et act (Onder that factors of transcription canonical of independently number the a through induces also signalling E-cadherin of fine-tuning bind to to Wnt– it E-cadherin leads and of AJ 2011), ability al., the the et that Schackmann activate nuclear likely 2007; to appears E- al., sufficient the of et not loss (Herzig is to However, signalling models 2006). al., mouse lead et in Koenig cadherin can 2006; of E- al., activity AJs et of the transcriptional (Coluccia are of downstream increased through what and activated Disruption But translocation cells are activated. loss? that of are cadherin pathways integrins capacity molecular when the invasive on AJs impact of that and pathways disruption signalling migratory and of number the (Creedon a by benefit governed be clinical these provide of cells ability to of capacity 2012). the harnessed Brunton, invasive and whether be migratory determine the can block to to further required inhibitors and disappointing, tumour is been solid of have work number currently results a the are in However, clinic which types. of the Src, advanced in extensively most of tested effectiveness The inhibitors being 2009). small-molecule their al., et are test Serrels these 2010b; and al., the et 2007; potential therapeutics, (Canel in identify to as al., anti-metastatic forward Such well move and system. new we et as immune as 2007), innate crucial interaction (Gaggioli the are al., of technologies et components stroma the with Wyckoff also 2011; future, host including al., et the tissue, Wyckoff with tumour pools. relationship behaviour integrin cell inside cancer and of monitoring deep E-cadherin the enable allow of will will this monitoring cancer Moreover, for and models tracking mouse genetic the the complex of target use to the be pathway new to a remains cancer. provide between of might spread crosstalk adhesions it the but E-cadherin-mediated established, controls such and and and/or How integrin 2008). integrin on by al., compromised of impacts et is (Mosesson and trafficking only factors transport growth endocytic not vesicular also aberrant functionality of but adhesions the deregulation in cadherin hallmark because The up-and-coming an 2012; the cancer, considered 2007). al., is influence et pathways al., (Bridgewater can recycling be invade et to and activity migrate shown their Ramsay to Arf been cells and and of have tumours, ability Rab trafficking the in this of deregulated control Many 2012). that al., adhesive GTPases their et thus and (Bridgewater control membrane to capacity E- plasma acts the also of at which availability dynamics integrins, their of the trafficking the are controlling in pathways same involved in the but role adhesions, cell–cell key flux. cadherin-mediated a constant in has is Endocytosis adhesions E-cadherin-mediated and integrin- h eeomn fnwitaia mgn ehooisand technologies imaging intravital new of development The snap- a only provides date to out carried research the of Much h rstl ewe elcl n elmti dein can adhesions cell–matrix and cell–cell between crosstalk The b ctnnptwy(ense l,20) nadto,ls of loss addition, In 2008). al., et (Jeanes pathway -catenin b ctnnt nlec uorprogression tumour influence to -catenin b ctnnat -catenin b b -catenin -catenin deintpsta a nlec uorcl behaviour cell tumour influence between crosstalk can indirect that Rho of of types complexity signals, survival regulation the adhesion integrin the with highlights interplay through 2012). and the and survival Giehl, signals and and GTPase (Menke growth controls E-cadherin of RhoGTPases tumour and loss from of stability resulting p120-catenin E-cadherin role activity Cytosolic emerging Onder both the the 2010; is controls al., interest also which Of et 2011). p120-catenin, Ma al., et of 2006; Wendt al., 2008; al., at et et colonization (Derksen and the sites angiogenesis phenotypes, metastatic tumour-associated survival, phenotype, other proliferation, of invasive as number functionality such a and E-cadherin on impact motile reduced can of more consequences a downstream suppressing in adhesions. cell of epithelial E- types in key by important between be triggered crosstalk and might or greater are plasticity that that and a perturb function events allow that cadherin biochemical will of interventions adhesion, understanding signalling upon of E-cadherin-mediated networks analysis associated promote is proteomic and to that Global phenotype pathways begin loss. metastatic acquisition E-cadherin can and the invasive with prevent we more or a reverse before might of required that strategies is develop signalling downstream hrp,s htnwteaetcsrtge a edvsdto of 2011). needs devised Weinberg, to and clinical be (Valastyan unmet response can cancers meeting advanced the strategies thus refractory as therapeutic disease, metastatic well new orchestrate target that as crosstalk so survival, events and is therapy, and molecular It dynamics progression the 2011). adhesion tumour how al., understand et of (Kim fully downstream as pathway more 2012), signalling to al., Hippo between et important the Goitre crosstalk by as For the (reviewed well AJs modulating uncovered. and for adhesions species being integrin oxygen candidates by reactive still emerging towards regulated as point are findings is recent that example, contacts mechanisms cell–matrix adhesions signalling cell–cell integrin-mediated E-cadherin-mediated and between Furthermore, crosstalk AJs. control that the in pathways be complexity signalling of can of level established. network proteins further the a be family indicating to Src, WASP by and remains phosphorylated cortactin function that both E-cadherin ligation Interestingly, integrin on in changes impact to and link can (Ratheesh they AJs how modulate and can junctional 2012), Yap, cortactin of WASP and and regulation proteins Ena/VASP the of the family in as and such factor regulators, actin key Actin calpains the homeostasis. a and also AJs (Noe as between is integrity interplay signalling cytoskeleton The AJ 2003). such on al., other et impact cleave Rios-Doria proteases, can thus of integrins, and For of by E-cadherin crosstalk. regulated number are this number which in a metalloproteinases, function a a that have example, also also suggest might is there intermediates However, to 3). (Fig. evidence RhoGTPases and drug of ILK be FAK, of Src, biomarker mechanism to the a in remains participates merely it it resistance. is whether although or expression E-cadherin response 2009), E-cadherin whether high Pintzas, established with revealed and patients have (Voulgari in cancer lung responses EGFR non-small-cell the better expression of in trials clinical E-cadherin erlotinib and resistance, inhibitor Moreover, drug to 2011). linked been has al., et (Schackmann lhuhw aefcse eeo h oeEcdei has E-cadherin role the on here focussed have we Although nti omnayw aehglgtdcosakmdae by mediated crosstalk highlighted have we Commentary this In -ahrnitgi rstl 399 crosstalk E-cadherin–integrin ta. 2001; al., et ¨ Journal of Cell Science ouca .M,Bnt,D,Dki,H,D iip,A,Ln .adGambacorti- and C. Lan, A., Filippo, De H., Dekhil, D., Benati, M., A. Coluccia, icii . addo . iael,F,Crzai . tide,C,Cngir,A., Conigliaro, C., Steindler, M., Corazzari, F., Citarella, I., Laudadio, C., Cicchini, rg,V . e aci,A,Mcek,L n eaa E. Dejana, and L. Machesky, A., A. Maschio, N. Del Hotchin, M., V. and Braga, A. Hall, M., L. Machesky, M., V. Braga, L. J. Bos, hitasn .J n aaeaa,A K. A. Rajasekaran, T., and S. Lim, J. E., Goka, J. T., C. Christiansen, Walsh, C., Lawson, C., Jean, O., J. Nam, L., X. Chen, J. W. Nelson, and B. D. Stewart, T., Y. Chen, T. Lecuit, and and F. C. P. Lenne, M. M., Rauzi, Frame, M., Cavey, B., Serrels, P., Timpson, D., Miller, A., Serrels, M., Canel, ogi . one,M,Mrtauh,V,Gre,M .adNlo,W J. W. Nelson, and L. M. Gardel, V., Maruthamuthu, M., Lowndes, N., Borghi, J. Behrens, and W. Birchmeier, F. Roy, Van and G. Berx, ae,M,Sres . nesn .I,Fae .C n rno,V G. V. Brunton, and C. M. Frame, I., K. Anderson, A., Serrels, M., Canel, azc . vlo . eai . aeia . ot,M,Slno . ml,J V. J. 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