mecha no transduction

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Mechanical frces inflence the grth andshape f virtall ever tisse and rgan inr bdies. Hever, little is knn abt themechanisms b hich individal cells sensethese mechanical signals and transdce themint changes in intracelllar bichemistr andgene expressin a prcess that is knn asmechantransdctin. It is cmmnl knnin the field that hen a phsical frce isapplied t the cell srface, it distrts the mem-brane crtex and then qickl dissipates intthe ctplasm1. Therefre, mechanchemicalcnversin mst nlccr in r near thesesites n the cell srface. As expected, srface-membrane receptrs sch as integrins andcadherins, hich mediate cell adhesin textracelllar matrix (ECM) scafflds and tneighbring cells, respectivel have acentral rle in mechantransdctin2.

Applicatin f a mechanical stimls, schas flid shear stress, t the cell srface acti-vates mechansensitive in channels, heter-trimeric G prteins, prtein kinases and thermembrane-assciated signal-transdctinmlecles; these trigger dnstream signal-ling cascades that lead t frce-dependentchanges in gene expressin3 (see the Revieb Hahn and Schartz103 in this isse).Bt these respnses are sall mediated bthe distrtin f specific adhesin receptrsthat link t the ctskeletn, rather thanb defrmatin f the lipid bilaer alne.

Fr example, endthelial cells sense flidshear thrgh a cellcell jnctinal cm-plex that cntains vasclar endthelial(VE)-cadherin and platelet/endthelialcell-adhesin mlecle 1 (PECAM1), inadditin t integrin activatin4. Mechanicalfrces that are applied directl t integrinssing micrmaniplatin r magnetictechniqes als alter in flx thrgh stress-activated in channels5,6 (see the Revie bChalfie104 in this isse), G-prtein-dependentcclic AMP signalling7, binding kinetics fstrctral mlecles8 (fr example, zxin),prtein-translatin-cmplex frmatin9 andactivities f prtein kinases, sch as p130CAS(als knn as BCAR1) and Src3,10. Ths,srface-adhesin receptrs and fcal adhe-sin prteins have a ke rle in mechanicalsignalling in varis cell tpes, and the field f

mechantransdctin fcses mainl n thecell srface1. Bt is this the hle str?

Mechanical stresses ill dissipate qicklafter passing thrgh the plasma membrane.Therefre, it makes sense t fcs n srfacesignalling if ne vies the cell as an elasticmembrane that srrnds a viscs r visc-elastic ctplasm that is filled ith ctskel-etal filaments that cntinsl deplmerizeand replmerize1113(BOX 1). Hever, analternative mdel f cell strctre sggeststhat this dnamicall remdelling ct-skeletn is als a hard-ired tensegrit

netrk that can prmte crdinatedchanges in cell, ctskeletal and nclear strc-tre in respnse t mechanical distrtin14(FIG. 1a). (Herein, the term hard-ired refers tctskeletal strctres that are stable enghas intercnnected nits t resist mechanicalstresses and thereb maintain shape stabil-it, even thgh the nderg cntinsdnamic remdelling at the mleclar level.)This mdel takes int accnt the bserva-tin that individal ctskeletal filaments canbear significant tensile and cmpressive ladsin living cells becase their strctral integrit

is maintained fr lnger than the trnvertime f individal prtein mnmers1517.

Ke t the celllar tensegrit mdel isthe idea that verall cell-shape stabilit andlng-distance frce transfer are gverned bthe level f ismetric tensin, r prestress,in the ctskeletn that is generated thrghthe establishment f a frce balance beteenppsing strctral elements (that is, micr-tbles, cntractile micrfilaments andextracelllar adhesins) (FIG. 1a). This ccrsbecase the cell can tense, and thereb stiffen,lad-bearing ctskeletal filaments relative tsrrnding regins f the ctplasm14,18,19.In this tpe f prestressed inhmgenesslid strctre, mechanical signals prpagatethrgh the ctplasm mch qicker thandiffsin-based chemical signals (BOX 1) (seethe Revie b Jaalk and Lammerding105in this isse). Hever, the viscelasticprperties f the ctsl that permeatesthis prestressed netrk can als inflencestress prpagatin t distant ctplasmicsites at sler timescales, and nn-cvalentprteinprtein interactins in the ctplasmmight gvern time-dependent stiffening andinelastic energ dissipatin in the cell20.

Becase integrins and cadherins arephsicall cpled t ctskeletal filamentnetrks that, in trn, link t nclear scaf-flds, ncleli, chrmatin and DNA insidethe ncles, mechanical frces that areapplied at the srface d mre than activatemembrane-signalling events the alsprmte strctral rearrangements deep inthe ctplasm and ncles21,22. This raises theintriging pssibilit that mechanical frcesapplied at the cell srface might act at adistance t prmte mechanchemicalcnversin in the ncles23, in additin

o p i n i o n

Mechanotransduction at adistance: mechanically coupling theextracellular matrix with the nucleus

Ning Wang, Jessica D. Tytell and Donald E. Ingber

Abra | Rarh n llular mhanoranduon ofn fou on how

xrallular phyal for ar onrd no hmal gnal a h ll urfa.Howr, mhanal for ha ar xrd on urfa-adhon rpor, uh

a ngrn and adhrn, ar alo hannlld along yoklal flamn and

onnrad a dan n h yoplam and nulu. Hr, w xplor h

molular mhanm by whh for mgh a a a dan o ndu

mhanohmal onron n h nulu and alr gn a.

PeRsPectives

NATuRE REVIEwS |Molecular cell Biology VoLuME 10 | JANuARy 2009 |75

f o c u s o n m e c h a n o t r a n s d u c t i o n

2009 Macmillan Publishers Limited. All rights reserved
http://www.uniprot.org/uniprot/P16284http://www.uniprot.org/uniprot/P56945http://www.uniprot.org/uniprot/P56945http://www.uniprot.org/uniprot/P16284


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t mechanchemical transdctin in thectplasm. Sch a hard-ired mechanismfr direct nclear mechantransdctin isparticlarl interesting becase mechanical-based signal prpagatin is mch faster thanchemical-diffsin- r translcatin-basedsignal prpagatin. Here, e highlight recentstdies that prvide direct experimentalspprt fr mechanchemical cplingbeteen the cell srface and the ncles anddiscss ptential mleclar mechanismsthat might mediate rapid frce transmissinthrgh the ctplasm t initiate nclear

mechantransdctin.

The hard-wred cell

Experimental stdies that are designed t testpredictins f the celllar tensegrit mdelhave cnfirmed that hen srface integrinsare directl stressed b appling large frcesith ligand-cated micrpipettes r magneticparticles, r b phsicall defrming cellsthat are attached t flexible ECM-cated sb-strates, immediate frce-dependent changesin internal strctres, sch as mitchndriaand ncleli, can be visalized deep inside the

ctskeletn and ncles, respectivel22,2426.Plling n integrins in cltred cells indcesthe mleclar realignment f individal actinstress fibres and ncleli, hich change theirpsitins and rerientate alng the nelapplied tensin field lines22(FIG. 1b,c). Frcesthat are applied t integrins als indce dis-placements f mitchndria and nclei p t20m aa frm the site f frce applicatin,hereas generalized defrmatin f the sr-face bilaer b plling n transmembranemetablic receptrs that are nt strngl cn-nected t ctskeletal actin bndles nl

prdces lcal effects at the cell srface24.Mechanical cpling beteen integrins andnclei is lst hen intermediate filamentsare disrpted22, and flid shear stresses thatdrag endthelial cells against their fixed fcaladhesins als displace intermediate fila-ments deep in the ctplasm27. As similarmechanical cpling can be shn in mem-brane-permeabilized cells in the presence fATP, hich spprts actmsin-based ten-sin generatin and the maintenance f pre-stress in the ctskeletn, these crdinatedchanges in strctral elements thrght the

cell, the ctplasm and the ncles are det direct mechanical frce transfer and nt tassciated chemical signalling events28. Thesefindings als have phsilgical relevanceas the can explain h mitchndria thatare lcated far frm the srface membranen ctplasmic micrtbles can sense andrespnd t mechanical strain b releasingreactive xgen species and activatingsignalling mlecles (sch as nclearfactr-B (NF-B) and vasclar cell-adhesinmlecle 1 (VCAM1)) that cntribte tinflammatin andathersclersis29.

Recent technlgical develpments thatenable stress mapping in the ctplasm fliving cells29,30 cnfirm that even smallmechanical defrmatins f srface integrinscan reslt in lng-range frce prpagatin,and stress cncentratins can be visalizedman micrmetres aa frm sites f frceapplicatin (FIG. 2a), inclding lcatins near

the ncles and at the ppsite ple f thecell30,31. Mst imprtantl, these mechanicalsignals indce rapid (50 m), as ell as at lcal sites(FIG. 2b). Strikingl, this mechanical respnseis 40 times faster than that indced b slbleepidermal grth factr32, as predicted bphsical mdels (BOX 1; FIG. 2c). Mrever,bth lng-range frce transfer and distantmechanchemical cnversin thrgh Srccan be inhibited b either disrpting the actinctskeletn r b dissipating ctskeletalprestress2932(FIG. 2a). Amazingl, mechani-cal cpling even ccrs beteen differentchrmsmes (FIG. 1c;Spplementar infr-matin S1 (mvie)) and beteen the mitticspindle, actin micrfilaments and srfaceintegrins in dividing cells33; this cplingmight cntribte t the cntrl f cell divi-sin rientatin, as ell as t the fidelit fchrmsme alignment.

physcal culg the cytlasm

The stdies discssed abve neqivcall

cnfirm the existence f lng-range frceprpagatin in living cells. Hever, thesestdies are mstl phenmenlgical and themlecles that link cell-adhesin receptrst the ctskeletn and ncles have nlrecentl been identified. Transmembraneintegrins link the ECM t the ctskeletnb clstering in specialized sbmembransanchring cmplexes (fcal adhesins), inhich the frm mleclar bridges b bind-ing t actin-assciated prteins, sch astalin, vinclin, zxin and paxillin34 (see theRevie b Geiger, Spatz and Bershask106

Box 1 | Mechatrasduct the fast track

Sss-w pp ps p s s psm

A small chemical, such as calcium (which has a diffusion coefficient of


3/8

a

b c1

2

3

4

5

8

7

6

9

Shear stressin this isse). Certain integrin sbtpes(sch as 64 integrin) als bind directl tintermediate filaments35. Cadherins link tthe ctskeletn b frming jnctinal cm-plexes that cntain -catenin and -catenin,hich bind actin filaments and intermediatefilaments, respectivel36. Althgh highldnamic, these mleclar cplings (seebel) are stable engh t fnctin astensed hard ires t prpagate mechanicalstresses frm the ECM t the ncles.

The LINC complex. Earl stdies revealedthat the intermediate filament vimentinbinds directl t the nclear lamina prteinlamin B and cnnects it t attachment sitesn the plasma membrane f reticlctes37,38.Mre recentl, a specialized nclear anchr-ing strctre fr ctskeletal filaments,knn as the LINC (linker f ncleskeletnand ctskeletn) cmplex, that cntains

nesprins, sn and lamin prteins3941, asidentified (FIG. 3).

The largest isfrms f mammaliannesprins (nesprin 1 and nesprin 2; alsknn as SyNE1 and SyNE2), and therelated ANC-1 in Caenorhabditis elegansand MSP300 in Drosophila melanogaster,are rd-like nclear membrane prteinsthat cntain an amin termins ith a cn-served calpnin-like actin-binding dmain,a hge central spectrin-like dmain, and acarbxl-terminal KASH (klarsicht, ANC-1,SyNE1 hmlg) dmain that mediates snprtein binding42. Nesprin 1 and nesprin 2n the ter nclear membrane cnnectactin micrfilaments t SuN1 (als knnas uNC84A) and SuN2 (als knn asuNC84B) n the inner nclear membrane;SuN1, in trn, binds t lamin A n thenclear scaffld3941,43,44. Shrter isfrms fnesprins are lcalized t the inner and ternclear membranes. These isfrms lack theactin-binding dmain bt might still inter-act ith ctskeletal cmpnents thrghspectrin repeats. SuN1 als cnnects thisanchring strctre t nclear pre cm-plexes (NPCs) and, it might therefre medi-

ate the mechanical cpling that has beenbserved beteen the tensed ctskeletnand nclear pres45. It is nknn, hever,hether SuN1 binds nesprin 1 and 2and theNPC simltanesl46. Nesprin 3, a smallerbt related famil member that lacks theN-terminal actin-binding dmain, cnnectst ctplasmic intermediate filaments bbinding t plectin 1 and interacts ith SuN1and SuN2 (ReFs 47,48). ANC-1 similarltethers nclei t the actin ctskeletnthrgh interactins ith the sn familmember uNC-84, and ANC-1 mtants have

defects in nclear psitining and nclearanchrage49. ZyG-12 and uNC-83, t therprteins that nl share the KASH dmainith nesprins, respectivel mediate tetheringf centrsmes (and, hence, the micrtblectskeletn) t nclei and cntribte tnclear psitining in C. elegans b binding

t uNC-84 (ReFs 5052). Ths, the hard-irefnctin f these LINC prteins seems thave been cnserved thrght evltin.

Lamins. Lamins A, B and C are inter-mediate filament-like prteins that frm amleclar netrk r nclear lamina n thencleplasmic srface f the inner nclearmembrane and are als fnd in the inter-nal nclear scaffld. Lamins have a centralrle in the cntrl f nclear rganizatinand gene fnctin53. These lamins can bedivided int t sbgrps: A-tpe lamins

(lamin A and lamin C) and B-tpe lamins(lamin B). A- and B-tpe lamins have dif-ferent rates f trnver in the ncleplasmand are thght t have different strctraland fnctinal rles53. Cells that are deficientfr A-tpe lamins have decreased viabilit,redced expressin f mechansensitive

genes and altered nclear mechanics inrespnse t mechanical distrtin, hereasdefects in lamin B1 d nt prdce simi-lar effects, hich sggests that the A-tpelamins might have a mre central rle inmechantransdctin54,55.

Lamins might cnnect t the geneticmachiner and t DNA bth directl and bbinding t ther nclear prteins, incldingemerin and lamin B receptr (LBR)53,5658.Emerin, hich binds t the LINC cmplexthrgh nesprins and lamins59,60, als assci-ates ith man different reglatr prteins

Fgur 1 | S -s pp. | compur mulaon

of a nulad ngry ll modl ha xhb mhanal ouplng bwn h ll, h yo-

klon and h nulu. th mag how h modl, anhord o h boom ubra a 2 pon,

bfor r applaon (lf panl), a 15 and 37 afr r applaon ha ornad o h

rgh (mddl panl) and afr h r rlad (rgh panl). th ll and nulu of h modl

rarrang n aordan wh h r, and rol bak o hr orgnal poon whn h for

rlad, a obrd n lng ll. b | Pha onra and orrpondng brfrngn mroop

mag ha how mmda molular ralgnmn n h yoklon and nulol whn r

ar appld o ngrn. th apparan of wh nulol n dord ll (arrow) nda mol-

ular ralgnmn n h rgon. | Molular onny of hromoom n nrpha and

mo ll, a rald by nrng a mrondl p no h nulu and pullng ou on nulolu

(panl 15) or hromoom (panl 69). th rul n h progr rmoal of all nrphahroman or ondnd hromoom a f hy wr bad on an la rng. Wh arrow nd-

a h ndl p and blak arrow nda h nulolu bng pulld ou. imag n par b ar

rprodud, wh prmon, from ReF. 22 (1997) Naonal Aadmy of sn. imag n par

ar rprodud, wh prmon, from ReF. 33 (1997) L.

P e r s P e c t i v e s



http://www.uniprot.org/uniprot/Q8NF91http://www.uniprot.org/uniprot/Q8WXH0http://www.uniprot.org/uniprot/Q9N4M4http://www.uniprot.org/uniprot/Q8I6B6http://www.ebi.ac.uk/interpro/IEntry?ac=IPR012315http://www.uniprot.org/uniprot/O94901http://www.uniprot.org/uniprot/Q9UH99http://www.uniprot.org/uniprot/P50402http://www.uniprot.org/uniprot/Q14739http://www.uniprot.org/uniprot/Q14739http://www.uniprot.org/uniprot/P50402http://www.uniprot.org/uniprot/Q9UH99http://www.uniprot.org/uniprot/O94901http://www.ebi.ac.uk/interpro/IEntry?ac=IPR012315http://www.uniprot.org/uniprot/Q8I6B6http://www.uniprot.org/uniprot/Q9N4M4http://www.uniprot.org/uniprot/Q8WXH0http://www.uniprot.org/uniprot/Q8NF91


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20

20

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0

0

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10

20

20

y

(m)

y

(m)

x (mm)

20

20

10

10

0

0

10

10

20

20

x (mm)

1,200

1,000

800

600

400

200

0

1,750

1,500

1,250

1,000

750

500

250

0

Stress field (baseline) Pa Stress field (+A, 10 min) Paa

b

50 nm

N

Plasma membrane

0 5 ns 1 s 5 s

0

2 s 3 s 4 s 5 s

10 ms 100 ms 1 s

c Mechanical force propagation

Chemical signal propagation

Nucleus

that are invlved in chrmatin mdificatin,transcriptinal reglatin and mRNAprcessing, and ith BAF prtein (alsknn as BANF1), hich binds directl tdble-stranded DNA56,6163. LBR alsbinds t mltiple inner nclear targets,inclding DNA, histne and varischrmatin-assciated prteins64.

Other crucial connectors. Mleclar cnnec-tins beteen nesprin, sn and lamin pr-teins are crcial fr the mechanical stabilitf the ncles and the hle cell, as cells ith

impaired nesprin 1, nesprin 2 r nesprin 3fnctinalit exhibit decreased mechanicalstiffness65. Mrever, stretching f rat cardiacmscle cells leads t changes in the spatialrganizatin f the intermediate filament(desmin)lamin netrk and t chrmatinalteratins at the nclear envelpe66. Again,this might have clinical relevance, as mta-tins f intermediate filaments (sch asdesmin and vimentin) that mechanicallcple srface-adhesin receptrs t nclearstrctres thrgh the LINC cmplex sb-stantiall alter cell-mechanical prperties,

as ell as cell, tisse and rgan fnctin67.Cnversel, mtatins f lamins r emerin,as bserved in patients ith EmerDreifssmsclar dstrphr ith the prematreageing disease prgeria, lead t lss f nclearshape stabilit, cell strctral abnrmalitiesand eventall t death68. Taken tgether,these reslts sggest that phsical cnnec-tins beteen ctskeletal filaments andthe LINC cmplex enable the entire cell,ctskeletn and ncles t fnctin as asingle mechanicall cpled sstem (FIG. 3).

Sme prteins, sch as lamins andmatrin 3, are fnd in the internal nclearscaffld r matrix that extends thrghtthe depth f the ncles and rientates mchf the nclear reglatr machiner23,6971.Lamins als bind a nclear isfrm ftitin72,hich cld ptentiall cntribte t thenclear strctre, given that the ctplasmicfrm f this large elastic prtein has

majr effects n mscle-cell elasticit73.Interestingl, actin and msin als seem tcntribte t nclear strctre and nclearfnctins, inclding chrmsme mve-ments and transcriptin7476. Emerin andBAF cnnect lamins t nclear actin77,78, andemerin preferentiall binds plmerized actinand stimlates its plmerizatin77,78. Thepresence f nclear actin and msin, andthe bservatin that intact ctskeletal andncleskeletal netrks that lack membranesphsicall cntract in vitro hen ATP isadded28, raise the pssibilit that actmsininteractins might als cntribte t nclearprestress and, hence, t the reglatin f frceprpagatin and transdctin in the ncles.

The genme itself is rganized int lps(5200 kb) and is partitined int fnctinalchrmsme territries thrgh the bindingf nclear matrix attachment regins(MARs), hich link nclear scafflds tdistinct DNA regins n the basis f theirseqences and gemetr79. Transcriptinand replicatin cmplexes might als help ttether interphase chrmsmes t the nclearmatrix80,81. The exact cmpsitin andstrctre f the nclear matrix is nknn,

althgh in additin t lamins and matrin 3,it cntains RNA and hetergenes nclearribncleprteins that are assciated ithmRNA prcessing79.

Genme rganizatin and nclear matrixcmpsitin change in respnse t cell andtisse differentiatin and t man envirn-mental factrs82. Man nclear prteins thatere riginall identified as DNA reglatrprteins might als have a strctral rle inthe ncles. Fr example, RuNX is bth achrmatin-strctre-mdifing prtein thatis crcial fr steblast differentiatin and a

Fgur 2 | Ms s. | Dpndn of long-dan for propagaon on

prr. two r map ar hown of a ll ha xpr a low baln ll of aldmon (lf panl),

whh downrgula yoklal prr whou drupng foal adhon or r fbr; and of

h am ll afr ramn wh 5g pr ml of h alum onophor A23187 (+A, 10 mn; rgh panl),

whh nhb aldmon and ror prr. in h map, appld r 17.5 Pa (a 0.3 Hz), h

larg arrow nda h bad momn dron, mall arrow nda h rla magnud of

r and rd rprn hgh r. b | Rapd (


5/8

Nuclear pore

TalinMyosin II

-actinin

Vinculin

F-actin Nesprin 1

Nesprin 2

Nesprin 3

SUN1SUN2

ACF7

MT

IF

Translocation 510 s

Diffusion 510 sGrowth factor

LINCcomplex

Emerin

Titin

Actin

Myosin

MAR

Geneactivation?

Force

Force

Chromatin

Collagen

Lamin A

Plectin

Nucleolus(rRNA?)

Stress wave propagation ~1 ms

Plasma membrane Nuclear envelope NucleusECM

Integrins

nclear scafflding prtein that links differentregins f chrmsmes, thereb facilitatingthe cmbinatrial cntrl f gene transcrip-tin8385. Ths, frces that are transmittedver the LINC cmplex and channelled vernclear scafflds might be fcsed directl ncrcial DNA reglatr enzmes and bindingfactrs (FIG. 3).

nuclear mechatrasduct

Becase stress-indced changes in mleclarshape, psitin r mvement (fr example,vibratin) can alter thermdnamic andkinetic prperties f lad-bearing mlecles19,frces that are prpagated t the ncles verdiscrete ctskeletal netrks might altermleclar self-assembl events86 and md-late nclear bichemistr b man pssiblemechanisms (FIG. 4). Fr example, nclearmembrane distrtin indced b frces thatare prpagated frm the cell srface in spread-

ing cells stimlates calcim entr thrghnclear in channels and indces assciatedgene transcriptin87. And, in flx thrghnclear membranes as measred b a patchclamp can be altered b mdlating theactin ctskeletn88. Althgh the mleclaridentit f mechansensitive in channels nthe nclear membrane are nknn, ne canpredict a mechanism b hich the channel ismechanicall cpled bth t the mechan-sensitive ctskeletn and t nclear scafflds,hich are apprximatel nine times stifferthan the ctplasm in living cells22. In thisscenari, plling n the cell cld distrt thechannel, prdcing channel distrtin relativet the channels stiffened nclear attachmentshen the ctskeletn is defrmed; thisalteratin f channel cnfrmatin can thenprmte in inflx.

As lamin A and emerin bind transcriptinfactrs89,90, and as emerin als interacts ithsplicing factrs63, frces transferred thrghthe LINC cmplex t these mlecles cldals directl alter gene expressin and pr-tein-isfrm expressin thrgh seqestra-tin r mdificatin f the transcriptin rsplicing factrs (FIG. 4a). As nel snthesized

transcripts are prcessed b the pre-mRNAsplicing 5 capping and 3 prcessing machin-er91, frces that are transferred t thesemlecles ver MARs cld als reglatemRNA splicing r prcessing92(FIG. 4b). Frexample, frces transferred t lad-bearingprteins in nclear scafflds cld ptentiallreglate gene activities as a reslt f phsicalnflding f their peptide backbne, hichin trn can prmte binding r self-assemblf ther nclear reglatr factrs. This frcetransfer might fnctin analgsl t thea in hich stress-indced distrtin f

ctskeletal titin inflences the nclear trans-lcatin f MuRF2 (als knn as TRIM55),hich is a ligand f the transactivatindmain f the serm respnse transcriptinfactr SRF93. Additinall, stress r strain innclear scafflds might change higher-rderchrmatin rganizatin, thereb restrictingr prmting the accessibilit f transcrip-tin factrs r ther reglatr factrs(sch as DNA r RNA plmerases, tpi-smerases and helicases) t specific geneseqences, hich cld similarlinflence gene transcriptin84.

As cells extend and rnd, nclear presphsicall expand and cntract and altertheir transprt rates. As this ccrs, nclearpres can mediate mechanchemical cnver-sin and cntrl f gene activities94. Nclearpres have been implicated in the cntrl fgenes that are tethered t these strctres,as ell as in the reglatin f histne H2biqitlatin and mRNA transprt95. Thecncentratin f stresses n NPCs thrghtransmissin ver the LINC cmplex cldtherefre bth phsicall distrt (fr exam-ple, expand) the size f the pre (perhaps

thrgh distrtin f the basket strctre)and change mRNA transprt, transcriptinalreglatin and chrmatin stats b defrm-ing the shape f mleclar cmpnents fthe pre and altering their chemical activities(FIG. 4c). Interestingl, nclear distrtin is aprereqisite fr entr int S phase dring cellccle prgressin, and it has been sggestedthat this might be de t enhanced transprtf large DNA-reglatr cmplexes thrghnclear pres96.

Interestingl, it is pssible that frcetransferred ver nclear scafflds t the

DNA backbne might directl alter genefnctin23. Man MARs lcalize t reginsf destabilized DNA, in hich mechanicalstrain can lead t melting f the dble helix79.Stress-indced DNA melting cld expsebinding sites fr transcriptinal reglatrsin a similar a t hich increased tistingstrain in the MYCgene prmter indcesmelting f far pstream binding elements(FuSE) and thereb stimlates binding f FBP(als knn as FuBP1) and FIR (als knnas PuF60) transcriptin factrs97,98(FIG. 4d).Intrigingl, the tisse specificit f genme

Fgur 3 | M m ecM s. A loal for appld o ngrn

hrough h xrallular marx (ecM) onnrad a foal adhon and hannlld o flamn-

ou (F)-an, whh bundld by -ann and mad n by myon ii, whh gnra prr.F-an ar onnd o mroubul (Mt) hrough an-rolnkng faor 7 (AcF7), and o nr-

mda flamn (iF) hrough pln 1. Pln 1 alo onn iF wh Mt and iF wh nprn 3

on h our nular mmbran. Nprn 1 and nprn 2 onn F-an o h nnr nular mm-

bran pron sUN1; nprn 3 onn pln 1 o sUN1 and sUN2. Owng o yoplam o-

lay, for propagaon from h ecM o h nulu mgh ak up o ~1 m. th un pron

onn o h lamn ha form h lamna and nular affold, whh aah o hroman and DNA

(for xampl, hrough marx aahmn rgon (MAR)). Nular an and myon102 (and nular

n) mgh hlp o form h nular affold, onrol gn poonng and rgula nular prr.

th for hannlld no h nular affold mgh drly aff gn aaon whn mllond

of urfa dformaon. By onra, ak ond for growh faor o alr nular funon by

lng hmal aad of gnallng, whh ar mdad by moor-bad ranloaon or hm-

al dffuon. LiNc, lnkr of nuloklon and yoklon; rRNA, rboomal RNA.




http://www.uniprot.org/uniprot/Q9BYV6http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4609&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4609&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.uniprot.org/uniprot/Q9BYV6


6/8

Chromatinloop

Transcriptionfactors

Cytoplasm

Nucleus

F F

F

Transcription factor

F

AAAA

AAAA

a Chromatin recombination b Nuclear matrix distortion

c Nuclear transport d DNA melting

Nuclear pore

Membrane-spanningreceptor

rganizatin and nclear matrix cmpsi-tin sggests that different cell tpes cld beprimed t react differentl t the same stim-ls thrgh differential tethering f genest lad-bearing nclear scafflds and, hence,t ke regins f stress cncentratin in thencles (fr example, as shn b MARs).

Ccluss

It is n clear that mechanical actin at adistance ccrs in living cells22,2933. This is

made pssible b the prpagatin f frcesand vibratinal energ thrgh transmem-brane integrins and cadherins, assciatedfcal adhesins and jnctinal cmplexes,and ctskeletal filaments that cnnect tthe ncles, its internal nclear scaffldsand linked chrmatin. Mechanical actin ata distance nl ccrs if the inpt energ iscncentrated r channelled acrss discretelad-bearing ctskeletal filaments, and thespatial distribtin and efficienc f frceprpagatin depends n differences in stiff-ness beteen these spprt elements (BOX 1).

It is fr this reasn that the fidelit andspeed f this intracelllar mechanical signal-ling respnse can be mdlated b alteringctskeletal prestress, hich cntrls the stiff-ness f tensed ctskeletal filaments, sch asstress fibres15,99 and intermediate filaments100,that span lng distances in the ctplasm.Frces that act n the ncles might prmtechanges in the shape, flding r kinetics fspecific lad-bearing mlecles r mightmdif higher-rder chrmatin rganizatin,

and thereb alter nclear prtein self-assem-bl, gene transcriptin, DNA replicatin rRNA prcessing all f hich are crcial frcell behavir. This niqe frm f mechani-cal signalling prvides a mre rapid andefficient a t cnve infrmatin ver lngdistances in living cells than diffsin-basedchemical signalling. It als helps t explainh mechanical frces simltanesl alterthe activities f mltiple mlecles at varissites in the ctplasm and ncles, a respnsethat is crcial fr cntrl f cell phsilgand tisse develpment19.

Ftre rk is needed t fll nderstandthe mleclar and biphsical basis fr thisdirect frm f nclear mechantransdctinand t nderstand h these prcesses areintegrated ith chemical diffsin-basedsignalling mechanisms. This ill reqireentirel ne methds fr prbing and anals-ing strctrefnctin respnses in livingcells, and ill prbabl reqire integratin fmleclar cell bilg methds ith nvelappraches frm engineering, phsics andnantechnlg.

Ning Wang is at the Department of Mechanical Science

and Engineering, University of Illinois at Urbana-

Champaign, 1206 West Green Street, Urbana, Illinois

61801, USA.

Jessica D. Tytell and Donald E. Ingber are at the

Vascular Biology Program, Departments of Pathology

and Surgery, Childrens Hospital and Harvard Medical

School, Boston, Massachusetts 02115, USA.

Donald E. Ingber is also at the Wyss Institute for

Biologically Inspired Engineering and the School of

Engineering and Applied Sciences, Harvard University,

Cambridge, Massachusetts 02139, USA.

Correspondence to D.E.I.

e-mail:[email protected]:10.1038/nrm2594

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hrby alrng lf-ambly of rgulaory omplx or ohr molular ruur ha ar mpor-

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ponn of h nnr nular por omplx, alrng opnng kn or modulang molular

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on h DNA ould lad o mlng (for xampl, a n At-rh ), and hrby fala bndng

of ranrponal rgulaor n a for-dpndn mannr.


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Environmental sensing by cells through focal adhesions.


nrm2593)

AcknowledgementsThe authors thank E. Xuan, A. Maniotis and S. Na for providing

FIG. 1a, FIG. 1b,c and FIG. 2b, respectively, and A. Maniotis and

J. Karavitis for permission to use their movie of chromosome

pulling. This work was supported by grants from the National

Institutes of Health (to N.W., J.T. and D.E.I.) and a Department

of Defense Breast Cancer Innovator Award (to D.E.I.).

DATABASESez G:hp://www.nb.nlm.nh.go/nrz/qury.fg?db=gn

MYC

ip:hp://www.b.a.uk/nrpro

KAsH

omim:hp://www.nb.nlm.nh.go/nrz/qury.

fg?db=OMiM

emryDrfu muular dyrophy

uPKB: hp://www.unpro.org

ANc-1 | BANF1 |BcAR1 |mrn |LBR | marn 3 | MsP300 |

nprn 1 | nprn 2| PecAM1 |n|tRiM55 | UNc84A |

UNc84B|vcAM1

FURtHeR iNFORMAtiON

ng Wg pg:hp://www.mh.uu.du/

onn/drory/fauly/profl.php?ur_d=1498

t igb lby:hp://www.hldrnhopal.org/

rarh/ngbr

SUppLEMEnTARY inFoRMATions l l:s1(mo)

all linkS are active in the online Pdf


82 | JANuARy 2009 | VoLuME 10 www..m/ws/mb

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=genehttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=genehttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4609&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ebi.ac.uk/interprohttp://www.ebi.ac.uk/interprohttp://www.ebi.ac.uk/interpro/IEntry?ac=IPR012315http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIMhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIMhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIMhttp://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=181350http://www.uniprot.org/http://www.uniprot.org/uniprot/Q9N4M4http://www.uniprot.org/uniprot/O75531http://www.uniprot.org/uniprot/P56945http://www.uniprot.org/uniprot/P56945http://www.uniprot.org/uniprot/P50402http://www.uniprot.org/uniprot/P50402http://www.uniprot.org/uniprot/Q14739http://www.uniprot.org/uniprot/Q14739http://www.uniprot.org/uniprot/P43243http://www.uniprot.org/uniprot/Q8I6B6http://www.uniprot.org/uniprot/Q8NF91http://www.uniprot.org/uniprot/Q8WXH0http://www.uniprot.org/uniprot/Q8WXH0http://www.uniprot.org/uniprot/P16284http://www.uniprot.org/uniprot/Q8WZ42http://www.uniprot.org/uniprot/Q8WZ42http://www.uniprot.org/uniprot/Q8WZ42http://www.uniprot.org/uniprot/Q9BYV6http://www.uniprot.org/uniprot/Q9BYV6http://www.uniprot.org/uniprot/O94901http://www.uniprot.org/uniprot/Q9UH99http://www.uniprot.org/uniprot/Q9UH99http://www.uniprot.org/uniprot/P19320http://www.uniprot.org/uniprot/P19320http://www.mechse.uiuc.edu/content/directory/faculty/profile.php?user_id=1498http://www.mechse.uiuc.edu/content/directory/faculty/profile.php?user_id=1498http://www.childrenshospital.org/research/ingberhttp://www.childrenshospital.org/research/ingberhttp://www.childrenshospital.org/research/ingberhttp://www.nature.com/nrm/journal/v10/n1/suppinfo/nrm5294.htmlhttp://www.nature.com/nrm/journal/v10/n1/suppinfo/nrm5294.htmlhttp://www.nature.com/nrm/journal/v10/n1/suppinfo/nrm5294.htmlhttp://www.nature.com/nrm/journal/v10/n1/suppinfo/nrm5294.htmlhttp://www.childrenshospital.org/research/ingberhttp://www.childrenshospital.org/research/ingberhttp://www.mechse.uiuc.edu/content/directory/faculty/profile.php?user_id=1498http://www.mechse.uiuc.edu/content/directory/faculty/profile.php?user_id=1498http://www.uniprot.org/uniprot/P19320http://www.uniprot.org/uniprot/Q9UH99http://www.uniprot.org/uniprot/O94901http://www.uniprot.org/uniprot/Q9BYV6http://www.uniprot.org/uniprot/Q8WZ42http://www.uniprot.org/uniprot/P16284http://www.uniprot.org/uniprot/Q8WXH0http://www.uniprot.org/uniprot/Q8NF91http://www.uniprot.org/uniprot/Q8I6B6http://www.uniprot.org/uniprot/P43243http://www.uniprot.org/uniprot/Q14739http://www.uniprot.org/uniprot/P50402http://www.uniprot.org/uniprot/P56945http://www.uniprot.org/uniprot/O75531http://www.uniprot.org/uniprot/Q9N4M4http://www.uniprot.org/http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=181350http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIMhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIMhttp://www.ebi.ac.uk/interpro/IEntry?ac=IPR012315http://www.ebi.ac.uk/interprohttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4609&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=genehttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene

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