www.landesbioscience.com mi:[email protected] Email: Yarden; Yosef to: *Correspondence http://dx.doi.org/10.4161/cam.22263 09/17/12 Accepted: 09/16/12 Revised: 07/04/12 Submitted: regulation transcription phosphorylation, factor, growth transition, mesenchymal Keywords: Israel Rehovot, Science; of Institute Weizmann Yarden* Regulation; Biological Yosef of and Department Tarcic Gabi Ben-Chetrit, Nir motile a of acquisition underlying phenotype switch novel a ERK-ERF-EGR1, 1 7:1, Migration & Adhesion Cell G.FSBJ21;26:1582 http://dx.doi.org/10.1096/fj.11-194654 2012; ERK-ERF J the to FASEB and response EGR1 EGF. in migration al. cell et mammary Y, drive Lu axis G, T, Pines Shay R, I, Avraham Amit G, Tarcic to: Commentary dein epithelial- adhesion, – 2 PMID:22198386; 92; – ;JnayFbur 2013; January/February 5; n eatssformation. fibrosis metastases organ and include which conditions, uha nebygnssadi tissue in and embryogenesis repair, in physiology, as normal pheno- such of context motile the in acquire types sheets Epithelial expression EGR1-centered program. thereby an stimulation nucleus, ERF of balanced the the tightly kinase permitting ERK export from to the repressor cascade of (MAPK) form that cascade active mitogen-activated a the unveiled allows underlying cell we the stimulated pathways contrasting which By which and growth. EGF, factors, migration, stimuli: cell serum mammary two induced mammary and human cells we employed study switch The the in ERK-ERF-EGR1 reported recently novel of light a in switches, late (transcription- and early independent) such phenotype. review motile we Here integrated fea- an of distinct tures confer and simultaneously (EGF), as factor they such growth cue, epidermal extracellular the an to in response activated are switches molecular several Apparently, migration understood. incompletely to are cells commit expression that gene division, programs and cell pathways to signaling commitment establish U ttaln tails. trailing edge, at adhesions leading of the disassembly simultaneous at and sites repeatedly adhesion forma- of entailing while tion process crawl, cyclic a cells engaging matrix which substrate a on requires cells epithelial lk h elcaatrzdcheck- well-characterized the nlike 1 G onso h elcce which cycle, cell the of points 03Lne Bioscience Landes 2013 swl sudrpathological under as well as elAhso Migration & Adhesion Cell 3 ossanti process this sustain To . Journal FASEB 2 oiiyof Motility h G1tasrpinfactor. of transcription induction the EGR1 novo to the de as nucleus well transcrip- as the cytoplasm, from ERF repressor the tional of translocation and phosphorylation mitogen-activated EGF-induced pathway, (MAPK) ERK composite kinase the involves of novel activation which a switch, reported factors, we proliferation, recently serum which cellular stimulate and EGF, which migration, stimuli, induces two and family. cells the contrasting epithelial (EGF) of mammary factor Employing molecules growth multiple epidermal with (BMPs), along factor factors morphogenic bone growth growth and transforming the hepatocyte latter (HGF), The the factors. include growth che- and as such mokines molecules, are switches soluble and the primarily of inducers microRNAs The proteins. mRNAs, newly involving synthesized and switches events, transcriptional early both switches, transcription-independent of myriad vessels, a mem- blood apply or cells basement lymph of across walls and branes invade also and otatl ocsb en fatnstress apply actin of fibers. and means by forces filopodia) contractile and (e.g., epithelial protrusions lamellipodia membrane locomotion, extend their cells sustain To otx fsvrlohrmolecular of core other the (see induction constitute motility several which switches, of the in context switch ERK-ERF-EGR1 the review ie,adspl h ag mut of amounts large the and supply adhesion exocytosis and of sites, vesicle turnover ensure of endocytosis cycles lated al wthsCnern Motile Conferring Switches Early 3 nprle,saitmoal regu- spatiotemporally parallel, In Phenotypes i.1 Fig. COMMENTARY ). 4 eo we Below 1

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©2012 Landes Bioscience. Do not distribute. 6/eA uui fNF is of it subunit phosphorylates a unclear, PI3K/AKT p65/RelA, remains that wiring possible exact the www.landesbioscience.com proteins, spectrum large effector both a of engaging controls by kinases pathway migration, other This by kinase-1 (Ser-473). the and by Ser-308) dependent residues (PDK-1; two on phosphoinositide AKT phosphor- of subsequent ylation and homology domain pleckstrin through (PH) the AKT to binding of direct activation by trigger generated PI3K PI3K-AKT Phosphoinisitides the conditions, stimulate cascade. certain to EGF mole- under permit RAS PI3K activated to as of cules coupling activation, as indirect well (PI3K), 3-kinase phosphatidylinositol with interact directly pathway. (PI3K) turnover ERK. adhesion migration. focal cell and and enables FAK proteolysis calpain of calpain-mediated of Subsequent complex another consisting of assembly that the molecule mediates activity, adaptor lamellipod an kinase as and functions its FAK with sites Along these extension. rapid of in resulting turnover sites, kinase adhesion adhesion to focal (FAK) phosphorylated, the localized the recruits Once mediate paxillin with activation. can that as ERK complex well a resulting in as MEK, and RAF ERK, kinases upstream with associ- ates physically paxillin protein complex hw htEFcnsiuaeRAC1 kinase, the stimulate and SRC been PI3K can involving has pathway a EGF through It GTPases that CDC42. small shown and the RHO of involves RAC, family filaments RHO and actin the Assembly of invasion. disassembly and and migration Rho AKT, NF of effectors downstream ttevnrlsd fmgaigcells. migrating of side formation ventral the invadopodia at for essential posts htpoe naintruhtsu bar- tissue through riers. invasion organelles propel that invadopodia, matrix-degrading of actin-filled, assembly the instigating eeae PI(3,4,5)P generates nte irto-euaigefco is NF effector pathway. the MAPK migration-regulating JNK Another the via migration rtis hc idtedephosphory- PI(3,4)P the product bind lated which proteins, h hshtdlnstl3-kinase phosphatidylinositol The xmlf otiuin ocell to contributions exemplify kB, 18 k eunilato fP3,which PI3K, of action Sequential rncito factor. transcription B 22 hc ieyehne cell enhances likely which lhuhEF cannot EGFR Although 3 17 , 19 2 n nain by invasion, and , n dpo TKS adaptor and 20 ,t directly to kB, sals sign- establish 23 Although 21 Two 16 ellrmtlt nrsos oTGF- to increased response in and motility cellular localization, junctional of E-cadherin loss increased expression, morphology, N-cadherin fibroblastoid acquisition a the of is example important One EGR1, by trans-inhibited and auto-inhibited ’ snail both and remo- isoforms factors snail chromatin deling three with all interact hand indirectly one example, the For on complex. remarkably is expres- sion E-cadherin of regulation FOXC2. factors the and Thus, E- by E2.2 goosecoid, indirectly the twist, or like KLF8), with and E47 bind of to group cadherin able a by repressors directly tightly either is controlled, E-cadherin of transcription The tmlt eeepeso program expression migration. and survival gene cell controlling a stimulate oaie pteimt olcinof collection cells. a mesenchymal to motile a epithelium of trans-differentiation polarized initiate in engaged to are order switches transcription-con- molecular distinct, trolled of number A hc oncst h ci cytoskeleton catenins. actin the via to (E-cadherin), connects transmembrane which cadherin the epithelial com- of protein are primarily and latter prised junctions The tight junctions. junctional adherens as cell-cell such complexes, epithelial of polarized disassembly pheno- the motile through to manifests types transition the of feature tensins 4. called Cten/tensin binders by F-actin of group replacement a below the of and exemplified loss are E-cadherin using switches roles such The vimentin, snail. for and fac- ETS-1 N-cadherin, including transcription tors, several as and fibronectin such mar- mesenchymal of kers, gain conco- with laminin-1, mitantly and E-cadherin, syndecan like involves MUC1, markers epithelial- epithelial it of the and loss as transition known mesenchymal commonly is n elahso oeue N-cadherin. molecule, adhesion to cell coupled calcium-depend- ent is another it of cases of upregulation some hallmark in and the EMT, considered is expression n E2 rca ciaoso h motile the of activators crucial ZEB2, and rncito-eitdSwitches Transcription-Mediated oso E-cadherin. of Loss ofrigMtl Phenotypes Motile Conferring 28 ’ rmtr(.. ni,ZEB1/2, snail, (e.g., promoter s elAhso Migration & Adhesion Cell n nteohrhn,ZEB1 hand, other the on and 24 h oso E-cadherin of loss The rncito is transcription s 1,2 nimportant An hsprocess This β. 27 26 25 es n codn oarcn report recent a expression. cten to upregulates RAS according mutant can- and lung and cers, cancers cancer, gastric breast in thymomas, prognosis poor a with ates issawal deietp fcell of type migration. adhesive ameboid called weakly migration, switch a cten-tensin the biases reciprocal to the migration. adhesion matrix, altering cell focal by promote Presumably, disassemble and thereby adhesions tail integrins, cytoplasmic the of from tensins displace siuae yEF n distinct factors). a serum proliferation by and cell (stimulated in EGF) culminating pathway a by migration contrasted cell (stimulated to and leading cascade cells, signaling epithelial mam- human mary employed we switches, control- motility ling unknown yet unravel To oiatwt oneuaino tensin a of 3. by downregulation followed with con- cten, comitant is of EGF upregulation transcriptional with mam- cells of mary stimulation Importantly, associa- are tions. cell-to-matrix they stabilize paxillin) to and thought vinculin (e.g., adhesion interact focal sites of proteins components several family with tensin Because niae htEKrte hnATis AKT than rather ERK that blocker, indicated PI3K a wortmanin, MEK and roles a inhibitor, U0126, used motility pharmaco- that a approach critical pathway, logical ERK the the by with played line activation. AKT In of kinetics strong prolonged but and ERK, of stimulation only transient and with a associated weak (serum) prolif- signal the erative relatively Reciprocally, profile. a transient by but displayed pathway cascade, PI3K-AKT EGF the ERK persis- of the and activation activated strongly EGF tently that arrays revealed protein reverse-phase using analyses hti rsn nteohrtensin other the in present proteins. is domain that actin-binding N-terminal har- COOH- no cten) called bors (also molecule; of 4 tensin-like tensin terminus tails 3, and 2 cytoplasmic tensins 1, Unlike adhesions. focal the at integrins to all members, localized four comprises family tensin h irRA20fml,wihthey loop. feedback bi-directional which a via family, repress of microRNA-200 members by the inhibited are phenotypes, 32 h eirclce-esnswitch. cten-tensin reciprocal The h R-R-G1Switch ERK-ERF-EGR1 The hsrcpoa wthealsce to cten enables switch reciprocal This 30 tni peuae n associ- and upregulated is Cten 4 Proteomic 33 The 31 29 3

©2012 Landes Bioscience. Do not distribute. a seta o elpoieain EGR1 proliferation, this cell and for serum essential was by FOSB while stimulation and FOS differed: followed IEGs the factors of serum transcription steps, and earlier in EGF Like tran- regulators. proto-oncogenic early of scription group wave immediate a earliest (IEGs), the The 37). micro-RNAs comprises ref. and in (reviewed newly mRNAs of waves to synthesized lead inevitably exemplified ERF, by as translocations, factor- protein modifications and growth ERF post-translational induced, potential Importantly, as partners. and 2-hybrid a proteins adhesion yeast cytoskeletal identified cytoplasm, which by the analyses, supported in promotes scenario directly once migration- or migration of genes, expression promoting represses and Possibly, ERF nucleus. sites the exited multiple subsequently underwent on ERF phosphorylation EGF, with stimulation 4 report, previous a migra- with cell line of In tion. and respectively, stimulator inhibitor, repressors a an as the TEL/ETV6 and identified ERF individual and growth inactivated members of systematically pathway, effector we ERK-MAPK main the factor-activated is factors these of activation EGF genes. early weaker with immediate in stimulation but resulted FOS FOSB, the namely and of complex, transcription components AP1 two we novo of de signals, transcription induced RAF. rapidly serum polarized that found of with reported ERK Consistent inhibition previously the a suppress AKT-mediated through to serum) pathway (i.e., mitogenic the cue enables crosstalk a reciprocal Presumably, while signaling. pathway, AKT ERK suppressing the of sig- favor in intracellular naling polarizes the that cue concluded motogenic we pathway, AKT the stimulated markedly U0126 of because application Moreover, migration. for essential .KluiR enegR.Tebsc fepithelial- of basics The RA. Weinberg R, Kalluri MA. 2. Nieto RY, Huang H, Acloque JP, Thiery 1. eas h T aiyo transcription of family ETS the Because ;PI:9888 http://dx.doi.org/10.1172/ PMID:19487818; JCI39104 119:1420- 2009; 8; Invest Clin PMID: J transition. mesenchymal 139:871-90; 2009; 007 http://dx.doi.org/10.1016/j.cell.2009.11. Cell development 19945376; disease. in and transitions Epithelial-mesenchymal References 36 on 35 34 ppoi n uo suppression. this tumor to and linked leading apoptosis pathways studies to the factor relevant transcription oncogenesis, of and majority proliferation addition, with EGR1 In cell associating reports stressors. with and along mitogens spectrum wide a of to responses early in cated ln ihslbemdaoso cell factor transforming growth and of hormone- (PTHrP) protein parathyroid mediators related the like soluble SerpinB2), migration and with (PLAUR targets along activator EGR1 plasmino- of gen the of list components (IL-8), two proliferation. the includes cell 8 example, on interleukin For effect an gene, but displayed disabled, one migration, when only decrease cell a on and primarily effects 14 significant the demonstrated reproducible of 10 Out genes, of factor. by bound majority transcription physically this the were EGR1, (11/14) which of genes 14 identified target interference RNA and assays gene reporter immunoprecipitation, matin cell permitted which migration. IEG, of EGF-induced transcription the first the represented oigo upesn cin fEGR1 of pro- actions migration suppressing the or as gene moting induce well and as suppress expression, the both EGR1, to of ability control rich uncovered the aha meitl fe G stimu- EGF after lation. ERK immediately the pathway via downregulation own undergoes which is microRNA-191, its transcript by to respective downregulated the binds and EGR1 promoter that addition, found directly In we transcription. BHLHB2 EGR1 and inhibit EGR3 DUSP4 pathway, whereas ERK-ERF EGR1: upstream the of inhibits negative regulators as function feedback genes three latter Interestingly, the BHLHB2. repressor the EGR3 and DUSP4, phosphatase MAPK such the migration, as cell of inhibitors included .Tri ,ArhmR ie ,Ai ,Sa ,L Y, Lu T, Shay I, Amit G, Pines R, Avraham G, 145: Tarcic 2011; Cell 4. edge. leading the at Life AJ. Ridley 3. obnto fDAary,chro- arrays, DNA of combination A irto nrsos oEF AE 02 26: http://dx.doi.org/10. 2012; J PMID:22198386; FASEB 1096/fj.11-194654 EGF. to 1582-92; cell response mammary drive in axis ERK-ERF migration the and EGR1 al. et http://dx.doi.org/10. PMID:21703446; 1016/j.cell.2011.06.010 1012-22; 38 oal,ER a enimpli- been has EGR1 Notably, elAhso Migration & Adhesion Cell a (TGF- ,bttels also list the but a), 39 Hence, ’ s xrsinporm seta o tumor for gene progression. essential complex transform programs into expression but switches signals unknown extracellular complex yet EGR1, similarly to addition eto h aodadZlaGoldenberg Zelda Chair. and Professorial Harold incum- Dr. the the of is bent the Y.Y. Medical Foundation. Adelson and Research G. Israel Sheldon Fund and Miriam the Research (DIP), German-Israeli Cancer Asset Cooperation the and Project Lungtarget Agreements, the Grant under European gram the Council, Commission Euro- Research the Institute, pean from Cancer grants National by the supported is research Our hc slkl civdb h hieof genes. choice the target by agenda, achieved specific large likely its is and which the EGR1 address of will paradoxes works future fibronec- Hence, tin). and TGF-beta1 (e.g., cell migration tran- and the factor) induces growth (e.g., endothelial it vascular angiogenesis hand promoting other scripts PTEN), the and on several and hand (e.g., apoptosis one of the Remarkably, hubs on tumors. controls of prostate EGR1 types of other progression and promotes this been that shows of evidence long wealth new a suppressor, has tumor a EGR1 considered the Although EGR1 and genes. of tier second ERF the and of of identity nuclear exact functions the cytoplasmic as many such the raise questions, with EGR1, of along targets switch, is ERF-to- downstream the state. of the pathway part understood, EGR1 cellular ERK well the motile relatively while a robust However, a to in cyto- transition culminating and events nuclear plasmic both embodies switch but roles. critical, regulatory with complex congruent all are targets, .Dzniwc A aisnN,Mchro I, Macpherson NB, Jamieson MA, Dozynkiewicz 5. nsmay h ERK-ERF-EGR1 the summary, In 2922 http://dx.doi.org/10.1016/j.devcel.2011. 11.008 drive PMID: 22:131-45; and 22197222; 2012; integrin Cell al. endosomes/lysosomes Dev promote progression. et late cancer to A, from Thun collaborate von recycling CLIC3 PV, and Berghe den Rab25 van J, Grindlay ’ Acknowledgments eet rmwr Pro- Framework Seventh s 40 ocial,in Conceivably, oue7Ise1 Issue 7 Volume ’ target s

©2012 Landes Bioscience. Do not distribute. www.landesbioscience.com 5 sieS oyD h ,CnlyL.Phosphorylation- LG. Cantley X, Zhu D, Joly S, Ishibe 15. kinase MAP both of Activation AJ. Ridley S, Potempa 14. DJ, Hartshorne Y, Sasaki Y, Wu G, Totsukawa 13. Johnson T, Yujiri JA, Witowsky AN, Abell BD, Cuevas 12. A. Wells DA, Lauffenburger P, Chang A, Glading 11. Weed KH, Martin AG, Ammer KE, Hayes LC, Kelley 10. HL, Elliott BA, Ballif W, Zhang EE, Er MC, Mendoza 9. Cammer W, Roosmalen van X, Song J, Rheenen van 8. for role A A. Wells JE, Murphy-Ullrich P, Chen 7. A. 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Biol an PMID:10644690; org/10.1074/jbc.275.4.2390 J via 275:2390-8; occurs pathway. and 2000; signaling motility kinase fibroblast ERK/MAP for calpain of required activation is receptor factor growth Epidermal for journal.pone.0013847 required http://dx.doi.org/10.1371/ PMID:21079800; 5: is 2010; e13847; and One PLoS regulation persistence. lamellipodia actin carcinoma to dynamic localizes of ERK1/2 sites by phosphorylated Cortactin PMID: SA. 41:661-71; 2011; regulatory 02.031 http://dx.doi.org/10.1016/j.molcel.2011. WAVE2 Cell the lamellipodia 21419341; Mol drives activating ERK-MAPK complex. by al. et protrusion G, Danuser 179:1247-59; http://dx.doi.org/10.1083/jcb. 2007; in Biol locally 200706206 Cell cofilin J PMID:18086920; PIP2 activates cells. EGF-induced and al. carcinoma et releases V, Desmarais hydrolysis X, Chen M, 134:689-98; 689 1996; Biol http://dx.doi.org/10.1083/jcb.134.3. 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Schaller VJ, Fincham MA, Westhoff NO, Carragher 16. pteilpeoye a e acr20;7:415-28; the http://dx.doi.org/10.1038/nrc2131 2007; against PMID:17508028; Cancer alliance Rev Nat an phenotype? progression: epithelial tumour in factors PMID:11160820 12:27-36; 2001; Cell Biol Mol mechanism. RhoA-dependent a trans- through mesenchymal differentiation growth to Transforming epithelial al. mediates et factor-beta1 ME, Engel CA, PMID: Lundquist 148:779-90; and 2000; invasion, Biol migration, http://dx.doi.org/10.1083/jcb.148.4.779 Cell breast 10684258; cell in J induces N-cadherin metastasis. cells of expression cancer Exogenous SA. http://dx.doi.org/10.1083/jcb. 139:1047- 139.4.1047 1997; PMID:9362522; Biol Cell G J 59; small cells. rho MDCK and in rac proteins by adhesion cell-cell PMID: of Regulation 97:8542-7; 2000; http://dx.doi.org/10.1073/pnas.97.15. A S 8542 U Proc Sci 10900013; cells. Acad cancer breast Natl progression negative cell-cycle estrogen-receptor of in pathway major kappa A activation: factor B nuclear factor-induced growth Epidermal J Am 294:G276- 00340.2007 2008; migration. http://dx.doi.org/10.1152/ajpgi. Physiol PMID:17991704; to 85; cell Liver 3-kinase Gastrointest epithelial Physiol phosphatidylinositol activation colonic Rac and promote stimulates Src factor through growth Epidermal PMID:16869750; Symp 70:167-71; Harb 2005; Spring http://dx.doi.org/10.1101/sqb.2005.70.014 Cold Biol invasion. Quant cell cancer (invadopodia), podosomes and Tks5, substrate SRC The L. http://dx. Cell J PMID:18606851; doi.org/10.1083/jcb.200801042 cells. 182:157-69; NIH-src 2008; in Biol formation podosome toward http://dx.doi.org/10.1083/jcb. 201009126 193:1275-88; 2011; PMID:21708979; Biol 3- Cell J p110 Phosphoinositide formation. by invadopodia al. mediated et pathway signaling Z, kinase Kouchi M, Kawamura 12:413-26; 2011; Biol http://dx.doi.org/10.1038/nrm3141 Cell PMID:21697900; Mol Rev Nat function. formation and characteristics, invadopodia: and podosomes oiiyadceoai ypopoii inln.J http://dx. doi.org/10.1242/jcs.023333 PMID:18287584; signaling. 121:551-9; phospholipid 2008; Sci by Cell chemotaxis and motility PMID:12932330; 13:1442-50; 2003; http://dx.doi.org/10.1016/S0960-9822(03)00544-X and protease- Biol ERK a p42 Curr as by FAK Src. regulation for protein: role adaptor novel targeting A MC. Frame MD, elAhso Migration & Adhesion Cell ‘ ins ’ and a regulates ‘ outs ’ of 0 uJ ao ,MroaD utlnT dmo ED. Adamson T, Mustelin D, Mercola V, Baron J, Yu 40. miR-183 MicroRNA S. Subramanian L, Li AL, Sarver 39. Shalgi I, Steinfeld O, Manor A, Sas-Chen R, Avraham 38. EGFR of regulation Feedback Y. Yarden R, Avraham 37. G. Mavrothalassitis Jr., G, Beal D, Sgouras L, Gallic Le 36. factor transcription ETS-domain The AD. Sharrocks 35. S, Zimmermann M, Bosse K, Schad K, Moelling 34. in switch new a Tensins: JS. Brugge G, Mouneimne 33. S, Lavi S, Carvalho T, Shay A, Citri I, Amit M, Katz 32. S, Ibrahem J, Cachat A, Albasri S, Al-Ghamdi 31. 36:31-4; 2004; Biol Cell Biochem J Int Tensin. SH. Lo 30. feedback ZEB/miR-200 The T. Brabletz S, Brabletz 29. YL. Hsu KH, Shen TC, Chen YH, Chen PL, Kuo 28. ewr fp3 5 n g1i eurdfor required Differ is Death Cell 10.1038/sj.cdd.4402029 Egr1 http://dx.doi.org/ cells. 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