cell adhesion adhesion molecule signaling mechanotransduction cell motility

Download Cell adhesion Adhesion molecule signaling Mechanotransduction Cell motility

Post on 14-Jan-2016

214 views

Category:

Documents

2 download

Embed Size (px)

TRANSCRIPT

  • Cell adhesionAdhesion molecule signalingMechanotransductionCell motility

  • Cell adhesion moleculesImmunoglobulin-likeCadherinIntegrinSelectinDystroglycan

  • IntegrinsAlpha/Beta heterodimersClosed/Open/Ligated statesCouple cytoskeletal and extracellular conformationsFocal complex

    Xiao et al., 2004InsideoutOusidein

  • Integrin signalingSurvivalFocal Adhesion KinasePI-3KSrc/Grb2, CrkRhoGAPPTEN/SHPPhosphatase and tensin homolog on chromosome 10PIP3->PIP2PI-3K antagonist

  • Integrin signaling: motilityJuliano 2002

  • CadherinsCell-cell adhesionAdherens junctionDesmosomeCatenin signalingp120 RhoGAP b Transcription factor a Cytoskeletal linkerDifferentiation/developmentTissue aggregation

    Juliano 2002

  • Cadherin SignalingCadherin/catenin signaling interacts with traditional growth factor receptors, incl wnt/frz/dsh and HGF/c-MetJuliano 2002

  • Immunoglobulin-likeUbiquitous class, CAMSeveral extracellular Ig like domainsNot antibodiesShort cytoplasmic tailAssociates with ankyrin/ spectrin cytoskeletonMAP kinasesFunctionDevelopmental guidanceImmune cell responseJuliano 2002

  • MechanotransductionMechanical conformational changeForceDeformationOpposition of internal and external forcesCAM-matrix adhesionCAM-cytoskeleton adhesionDeformability of series structures

  • Elastic DomainsEGFFibronectin (FN)Immunoglobulin (Ig)Complement likeComplement likeIgEGFCN3D, UIUC Theoretical and computational biophysics group

  • Mechanical conformational changesMechanical energy disrupts H-bondingModular elasticitynm stretch100%+ strainpN forceGao et al., 2002 PNAS

  • Cell growth-substrate interactionSubstrate chemistryLigand matchingIntegrin/CAM mediated differentiationSubstrate mechanicsImproved differentiation on elastic substratesFewer stress fibers on softer materialsYeung et al 2005

  • MotilityMotility vs. contractionPolymerization systemsActinTubulinFilament motor systemsActin-myosinMicrotubule-kinesin/dynein

  • Structural reorganizationMotion of focal adhesions (white) and surrounding gel (red) in corneal fibroblasts. Petroll et al 2003

  • CrawlingPseudopodiaLammelapodiaFilopodia

    Actin filament dynamicsDirectional polymerizationTreadmillingPhotolabel actinmonomers2 minutesCell moves relative to actin

  • Actin: polymerization dependent motionDisk shapedAdenine nucleotide bindingATPase activityNucleotide exchangePromoted by ProfilinInhibited by CofilinFilament formationBarbed/Pointed endMyosin S-1 decorationADP maturation

  • Actin filament polymerizationAsymmetric exchange of monomersMyosin fragment

  • Filament regulationExchange proteinsProfilinPROmotes filament growth towards barbNucleotide exchange factorCofilinADP-Actin bindingFilament repairMonomer recyclingCofilin disassembles ADP-actinProfilin regenerates ATP-actin

  • Monomer recyclingFacilitates treadmillingMembrane extensionATP-ADP conversion as filament maturesCofilin disassembles ADP-actinProfilin carries ATP-actin to leading edge

  • Rho family GTPasesGTP dependent cofactors, like Ga subunitsRho Kinase, mDia, Components of shape-dependent processesMotility, cell cycle, phagocytosis

    Heasman & Ridley 2008

  • Rho family GTPasesRhoStress fibers, integrin, selectinRacLamellipodia, growth factorscdc42Filopodia, cytokines

    Constitutively active cdc42 Rac RhoNormal cell

  • Rho family signaling diversitycdc42WASPIRSp53mDia2PAKLIMKcoflinActinturnoverARP2/3ActinpolymerizationActinbranchingLamellipodiaFilopodiaRacWAVEmDia2PAKLIMKcoflinActinturnoverARP2/3ActinpolymerizationFilopodiaforminRhoRhoKStress fiberMLCKMLPmyosin

  • MicrotubuleRegular array of a/b dimersSpontaneous tube formationPolar

  • Motor ProteinsMyosin-actinKinesin-tubulinDynein-tubulin

  • Motor step cycleOne headTwo head Hand-over-hand

  • Motor step systemsMtK1MtK1TMtK1DPMtK1DK2MtK2K1TMtK1DPK2DK1MtK1DPK2MtTTPPDShape ChangesWeakBinding K2StrongBinding K2MyosinKinesin

  • Kinesin/Dynein motilityVesicular transportKinesinToward +Away from nucleusDyneinToward Toward Nuc0.1-1 um/s

  • Myosin motilityCytoplasmic streaming (plants)Transport of ER along actin tracks60 um/sMuscleSpecialized bipolar myosin filamentsOpposing motion in adjacent actin filaments1-10 um/s

  • Highly ordered filamentsCrystalline polymerization facilitates molecular interactionMaximize density of force generating elementsWoodhead et al 2005Double-headed MyosinJ structure on filament surface

  • Regulation of force (smooth muscle)Thick filament regulationRegulatory myosin light chain phosMyosin light chain kinase (MLCK)CalmodulinSlow, sustained

  • Regulation of force (striated muscle)Thin filament regulationSteric availability of actinTropomyosinTroponin I,C,TCooperativeRapidWeak myosin bindingStrong myosin bindingActinTropomyosin

Recommended

View more >