Cell$Movement$$$Figure 19-52a Molecular Biology of the Cell (© Garland Science 2008) F-ac%n'Focal'adhesions'Last$class:$$Integrins$in$focal$adhesions$interact$with$fibronec:n$in$the$ECM'The'stable'a2achment'of'cells'to'the'ECM'o8en'occurs'through'hemi-desmosomes$(in'epithelial'cells)$and$focal$adhesions$(in'non-epithelial'cells).'Focal$adhesions$are'macromolecular'complexes'through'which'mechanical'force'and'regulatory'signals'are'transmi2ed.'Integrins$are'the'most'prominent'adhesion$receptors'found'within'focal'adhesions.'Focal$adhesion$integrins$mediate'a'linkage'between'fibronec%n'in'the'ECM'and'the'intracellular'ac%n'cytoskeleton.'Integrins'and'focal'adhesions'have'been'well-studied'in'fibroblast'cells.'Table 19-4 Molecular Biology of the Cell (© Garland Science 2008) Integrins'are'heterodimers.'Humans'encode'~18'alpha'and'~8'beta'subunits.''Integrin'heterodimers'interact'with'mul%ple'ligands,'including'fibronec%n,'to'play'key'roles'in'signaling,'morphogenesis,'and'movement'in'diverse'cell'types'(fibroblasts'are'the'best'characterized).'Different$integrins$interact$with$dis:nct$protein$ligands$Figure 19-45 Molecular Biology of the Cell (© Garland Science 2008) Integrins$interact$with$the$extracellular$matrix$and$with$the$ac:n$cytoskeleton''The'integrins'provide'a'physical'link'between'the'ECM'and'ac%n'filaments.'Integrin'associa%on'with'ac%n'occurs'through'ABPs'such'as'talin'and'vinculin.'Many'stress$fibers$are'anchored'to'focal'adhesions'(as'you'saw'in'the'first'slide).''''(e.g.,'fibronec%n)'Figure 19-48 Molecular Biology of the Cell (© Garland Science 2008) Integrins'therefore'mediate'inside-out'and'outside-in'signaling.'Inside-out'signaling'means'that'the'cytoskeleton'on'the'inside'of'the'cell'can'influence'binding'to'the'extracellular'matrix.''Outside-in'signaling'means'that'interac%ons'with'the'extracellular'matrix'can'alter'the'organiza%on'of'the'cytoskeleton'within'the'cells.'The'ability'of'integrins'to'engage'both'intracellular'and'extracellular'components'is'important'for'cell'signaling'and'mo%lity.'Integrins$adopt$mul:ple$conforma:ons'Most'integrins'exist'in'two'conforma%ons:'a'low'affinity'(inac%ve)'form'and'a'high-affinity'(ac%ve)'form.''These'two'forms'reflect'changes'in'both'the'cytoplasmic'and'extracellular'domains'of'the'protein.'Figure 19-49 Molecular Biology of the Cell (© Garland Science 2008) Integrin$associa:on$with$the$cytoskeleton$is$influenced$by$transme m br ane$signaling$cascades'Integrin'func%ons'are'modulated'by'mul%ple'signaling'pathways.'For'example,'phosphoryla%on'by'receptor'tyrosine'kinases'influences'talin'and'thereby'ac%vate'integrins.'Integrin$clustering$also$ini:ates$signaling$pathways$that$involve$several$familiar$players'In'par%cular,'the'dynamic'assembly'and'disassembly'of'focal'adhesions'plays'a'key'role'in'cell'migra%on.'Integrins'that'have'been'engaged'by'proteins'in'the'ECM'(e.g.,'fibronec%n)'signal'to'non-receptor'tyrosine'kinases'called'focal'adhesion'kinase'(FAK)'and'c-Src,'which'are'involved'in'ac%va%ng'PI3K'and'Rho-family'GTPases.'These'signaling'cascades'intersect'with'pathways'downstream'of'receptor'tyrosine'kinases.'As'a'result,'a'diverse'group'of'cellular'responses'(prolifera%on,'ac%n'rearrangements,'transcrip%on)'occur'downstream'of'integrin'ac%va%on'in'focal'adhesions.'(FAK,$c-Src)$h2p://www.youtube.com/watch?v=r6o4uY_MVkE'Cell$movement$is$a$highly-coordinated$process'Ac:n$assembly$drives$membrane$protrusion$at$the$leading$edge$of$a$migra:ng$cell'T.Pollard'Because'ac%n'polymeriza%on'at'the'leading'edge'is'coupled'to'membrane'protrusion,'it'has'been'hypothesized'that'the'assembly'of'ac%n'filaments'in'the'network'abuang'the'plasma'membrane'generates'the'force'that'pushes'the'membrane'forward.'If'you'would'like'to'present'this'slide'during'the'lecture,'please'volunteer.''If'you'are'especially'eager,'you'could'email'me'before'class.'Figure 16-90 Molecular Biology of the Cell (© Garland Science 2008) The$ac:n$network$in$lamellipodia$undergoes$both$treadmilling$and$retrograde$flow'As'ac%n'filaments'are'nucleated'at'the'leading'edge'of'a'fibroblast,'the'en%re'network'of'filaments'is'thought'to'flux'backwards'towards'the'interior'of'the'cell'in'a'process'called'retrograde$flow.''Retrograde'flow'During'this'process,'some'of'the'force'generated'by'ac%n'polymeriza%on'at'the'membrane'pushes'the'whole'network'back.'At'the'same'%me,'depolymeriza%on'occurs'at'the'(-)'end'of'network'filaments'by'cofilin.'Thus,'retrograde'flow'involves'a'treadmilling'ac%n'network'moving'toward'the'interior'of'the'cell.''Re-visi:ng$the$retrograde$flow$of$ac:n$using$fluorescence$speckle$microscopy'Ron'Vale’s'lab'(UCSF)'Verkhovsky'Lab,'PLoS%One,'2008'Visualizing$ac:n$dynamics$at$the$leading$edge'Burne2e'&'Lippinco2-Schwartz,'2011'RFP-ac%n'Membrane$protrusion$must$be$coordinated$with$cell$adhesion$during$directed$migra:on'Model:$Membrane$protrusion$and$cell-substrate$aPachments$are$important$for$mo:lity'''''''Cell'mo%lity'occurs'in'several'steps:'(1) The'first'step'involves'the'forward'protrusion'of'the'lamellipodium,'which'is'driven'by'the'force'of'ac%n'polymeriza%on'(as'we'saw'earlier).''(2) The'second'step'is'adhesion,'in'which'the'lamellipodium'interacts'with'the'substrate'in'front'of'the'cell,'forming'structures'such'as'focal'contacts.''(3) The'third'step,'cell$body$transloca:on,'has'been'postulated'to'occur'via'a'dynamic'network'contrac%on'model.'In'this'model,'myosin-mediated'contrac%on'of'the'ac%n'network'at'the'junc%on'between'the'cell'body'and'the'lamellipodium'pulls'the'cell'body'forward.''(4) The'fourth'step'is'de-adhesion$and'tail$retrac:on,'during'which'the'rear'of'the'cell'moves'forward.'D.Drubin'Figure 16-86 Molecular Biology of the Cell (© Garland Science 2008)
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