Stressing the limits of focal adhesion mechanosensitivity Patrick Oakes and Margaret Gardel - PDF document

Stressing the limits of focal adhesion Margaretadhesion Biologywww.sciencedirect.com interfacebetweenlamellipodiumandlamellaella21].Feedbackadhesionassemblypromoteactivationadditionallamellipodialprotrusionthroughadhesionsuchch32].Withinthelamella,myosinactivitydrivesfocaladhesiongrowthandrecruitmentfocaladhesionproteinssuchzyxin,pY31PaxillinandpY397FAKK28,33processtermedÔmaturationÕÕ1] (Figuresandadhesionsadhesionmechanosensitivity Figure 1 Lamella ActinFilamentMyosin IINascentAdhesionMaturingAdhesion-actinin AssemblyStabilizationMaturation Tension ~ 1 nN Current Opinion in Cell Biology nascentformation(middle)adhesionthelamellipodium/lamellaplaque.bothcorrelatedretrogradeflow.criticalthresholdadhesionindependentintracellular Figure 2 Polymerization ForceAssembly FAK-actininVinculinIntegrinTalin ActinPlasma MembraneTraction Force Contractile Force ,v Friction CoefficientForce ~1 nNIntegrin-ECMActin-AdhesionCurrent Opinion in Cell Biology transmissionadhesion(left)engagement(middle).complexdynamiceffectivecoefficientsappliedstrengththeinterfaceincreasing www.sciencedirect.comCurrent growtheyelongatecentripetally,typicallylengthfewmicrometers,whilemaintainingconstantwidthThisgrowthrateidenticaltheratemyosinII-dependentactinretrogradeßoww34,35andoccurssimultaneouslywiththeassemblyradialstressÞbertheadhesionplaqueue36,37Interestingly,theratelamellarretrogradeßow,radialstressÞberassemblyandadhesiongrowthunaffectedevenwhenmyosinactivitypartiallyinhibitedsuchthatintracellulartensionreduced80%%35]. Thus,focaladhesiongrowthratestronglycorrelatedretrogradeßowrateFigurebutnotforce.Similarly,tensioninsufÞcientforfocaladhesionmaturationwhenradialstressÞberassemblyimpairedd36]. Thus,myosinII-mediatedmaturationdependsthestructureanddynamicsthelamellaractincytoskeleton,butnotsensitivechangesintracellularforce.withincontributeshapemaintenancetenance11,38]. MatureprecursorsÞbrillaressentialremodelingÞbronectinin1,39]. FibrillaradhesionsunderlargeintracellulartensionsÞbersrs36].While less studiedprocessesoccurringassembly,adhesiondisassemblycomponentmigrationdistinctprocesss40–43]. Though adhesionssuffermechanicalrupturesubstratee44], it is notbelieveddominantmechanismadhesiondisassemblyly45].Force transmission at focal adhesionsFocal adhesionsactivelygenerateratherregulatetransmissioncytos-keletongeneratedcytos-keletondriverearwardmovementknownretrogradeEngagementfocaladhesionsretrograderateses46–48] and an increase in traction stresses [27] andtherebythoughtÔmolecularclutchÕchÕ49,50].The ÔclutchengagementÕinvolvesincreasesdensityafÞnitybindinginteractionsspanningcytoskeletonminimum,stabilizationrequires(i.e.lifetimedecreasesappliedintegringrin51]. Duringstabilization,ECMbondss31] and actin–vinculinin34] interactionsstrengthening.Becausebindingdynamics,transmissionadhesionstabilizationmodeleddynamicfrictionion52–54] (Figure 2). The stabilizationadhesionsinterfaceintegrincomparedactin/focaladhesioninterfaceoccurstensionsons31] (Figure 2). Once stabilized,adhesionstransmitwidecytoskeletonton55].SuperresolutionmicroscopyrevealeddistinctstratiÞcationlayersproteinswithinadhesionon7],with the most interestingproteinsbeingwithinadhesionn7,56] andvinculin [57]. In the case of talin, stretchingadditionalvinculinbindingmechanismforce-dependentrecruitmentment17]. Vinculin stretch-implicatedadhesionstability,adhesionon34,57,58]. While thesemolecules are often referredmechanosensors,mechanismsregulatingstretchingwithinelucidated.servedestablishdynamicsproteinswithinadhesion.nanoscaleshownbothexhibitdifferentbehavioradhesionsons59], consistenttensionintegrinsadhesionsons60]. Similarly,transientstretchingindivid-moleculeswithinadhesionsreported,bindingunbindingproteinsadhesionesion61]. Stretchingwithinalsopotentiallydownstreampathways,p130Casas16].Is focal adhesion maturationmechanosensitive?Historically,adhesionmaturationinterpretedevidencemechanosensitivity.However,myosinalsoimpactsstructurecytoskeleton.Myosincross-linksF-actinretrogradeRecenttensionrequiredmaintainradialstressÞberassemblyy35]. Over a wideintracellularperturbations,adhesionretrogradee34,35,36].Moreover, actin crosslinkingadhesionstabilization,compositionalmyosinintracellular90%%21]. Finally, in the absence ofradial stressÞbers,tensioninsufÞcientdrivematurationion36]. These results have led to theidea that the actin architectureimportantÞberstemplatesfocall36].While there exists some evidenceadhesionunderexternalnal13], it shouldbe noted that the timescaleconsistentadhesion Biologywww.sciencedirect.com stressess62]. On shorterestablishesmechan-equilibrium,adhesionsexhibitt55]. Stressassemblyadhesionforce-dependentrecruitmentproteins,zyxin-actinininin63].Adhesion size does not regulate local celltraction forceThe connectionbetweenadhesionsizestresslongstandingquestionindicatedpositivecorre-e-14,64], an inverse correlationelation65] as well as morecomplicatedrelationshipsps66]. Our own work showedthat a correlationadhesionperiodadhesionesion55]. In the absence of growthpredictorctor55]. Moreover,correlationimplycausality,perturbationsfacilitateforcesadhesionsforcesadhesionss36,55,62]. Thus, focaladhesionpredictorconsideringroleadhesionsregulatingoveralltraction,previousstudiespositivecorrelationstotalcontractilegeneratederated67–69]. An increase in the number of adhesions,however,accompaniedsimultaneousregulatoryparametersspreadd70,71]. Additionalindi-regulatorypathways.importantdistinguishbetweenforcesstrength.cell-generatedforcestransmittedsubstrate.Adhesionrequiredphysicallyadhesiondataindicateweaklydependentadhesionleastt19,55,72].A broader lesson from these studies is the importanceconsistentbenchmarksqueryingphysicalperturbationsparametersbiologicalproblems.instance,importantnotdeducecausalrelationshipspurelycorrelativemeasure-mentscorrelationbetweenfocaladhesionforceimplycausation).alsoessentialconsideralternateinterpretationsmechan-perturbations,controllingconcomitantchangessubstratestiffnessconcomitantlyimpactgeometry).helpfulconsiderscale,global,interactiondeterminingquantitativemeasurementsforce-sensitiveprocessesmoleculardirectlyImplicationsinsightsregulationcurrentenvironmentalregulationnotclear.implicationadhesionsizelacknotcytoskeletalcontractility,organization.predictorcontractility.mechanosensitivityfocaladhesionsplayedrolecurrentmodelsstiffnessexternalimportantmechanosensi-dependingadhesioncompositionn73] and only occur underlimitedAlternately,mechanosensitivitycouldpartscytoskeletonadhesionassemblyindirectly.Moreover,myosinconsequencesothermechanicalcurvature.Finally,suggesteddynamicsimportantrigiditysensingng74]. 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