5 junctions cell membranes epithelium2007post

5 junctions cell membranes epithelium2007post - Epithelial...

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Unformatted text preview: Epithelial Barriers: epithelial cell adhesion and cell junctions “good fences make good neighbors” Steve Sugrue, August 28, 2007 Epithelium • An epithelium is comprised of cells which are linked together both mechanically and functionally by close adhesion. • This epithelial sheet usually sits on a surface or lines the lumen of organs. Big Questions • How do epithelial cells stick? • How do adhesions function? • How do epithelial cells let go? • What is so special about epithelial junctions? The first epithelium morula blastocyst Outside Inside Outside Inside Food in Stuff out Epithelium is continuous Outside Inside Food in Stuff out Epithelial barrier • Epithelia usually constitute the barrier between two physiologically distinct compartments, separating the lumen from the underlying connective tissue/vasculature. Cell­cell and cell matrix adhesion • Non­junctional­ adhesion molecules are distributed diffusely in the plane of the membrane. • Junctional­ adhesion molecules are clustered into morphologically identifiable structures Classes of cell adhesion molecules • Cell­Cell adhesions – Calcium­dependent adhesion Cadherins – Calcium­independent adhesion N­Cams Selectins • Cell­matrix interactions Integrins Cadherins • Single transmembrane domain glycoproteins that form homotypic interactions between cells • In the presence of calcium, cadherins dimerize and interact with dimers from adjacent cells • Aggregation of cadherins appears to be dependent on rho GTPases Cadherins • • Cadherins: Structure and Function http://www.cdb.riken.jp/en/05_development/0505_cadherins01.html Cadherins • • • • • Calcium dependent Variety of distinct genes Extensive splicing Homophilic Bind to actin cytokeleton via catenins Differential expression of adhesion molecules allows sorting Cadherins: Structure and Function http://www.cdb.riken.jp/en/05_development/0505_cadherins01.htm l Differential expression of adhesion molecules allows sorting Loss of adhesion molecules allows invasion Lo s s o f E­c a d h e rin o b s e rve d in tu m o r d e ve lo p m e n t o f a va rie ty o f tum o r typ e s Me c h a nis m s in c lu d e : – Muta tio n o f E­c a d h e rin g e ne (c o lo re c ta l, g a s tric , a nd b re a s t) – P ro m o te r ina c tiva tio n b y h yp e rm e th yla tio n (b re a s t, g a s tric , p ro s ta te , a nd le uke m ia ) – T ra n s a c ting p a th wa y s in vo lving re p re s s io n a t c a d h e rin’s p ro m o te r E p ith e lia l Junc tio ns • • • Ba rrie r Ad h e s io n/a nc h o ring C o m m unic a tio n E p ith e lia l BAR R IER Junc tio n • T ig h t Junc tio ns Zo nula O c c lud e ns Tight junctions (zonula occludens) • Forms a barrier between cells (can be measured by resistance) • Creates a gasket­like seal separating the apical and basolateral domains • Most apical junction in the lateral membrane of epithelial cells • Freeze fracture of tight junctions revealed ridges within the membrane that corresponds to sites of contact between cells Tight junction Epithelial ADHESION Junctions • Ad h e re ns junc tio ns • Desmosomes • Hemidesmosomes Zonula adherens • Belt­like junction which circumscribes the cell, usually near the apical end. • Mechanically link cells to one another: • Anchor the thin filaments of the cell cytoskeleton. Zonula Adherens (ZA) • Integral membrane proteins cadherins • Plaque proteins α, β, and γ catenins vinculin a­ actinin plakoglobin • Cytoskeleton actin Desmosomes (macula adherens) • Stable cell­cell junctions formed along the lateral membrane • Most commonly foundon stratified squamous epithelium (i.e.skin) • Characterized by an electron­dense plaque on each side of the membrane • 10 nm keratin filaments attached to plaque Desmosome • Anchor the intermediate filaments of the cell cytoskeleton • Mechanical linkage between epithelial cells • Not a belt, but a spot­like junction. De s m o s o m e • Inte g ra l m e m b ra ne p ro te ins c a d h e rin s (d e s m o g le in, • P la q ue p ro te ins d e s m o c o llin) d e s m o p la kin p la ko g lo b in • C yto s ke le to n in te rm e d ia te fila m e nts (ke ra tin) Cell­matrix interactions • Inte g rin fa m ily – S in g le ­p a s s tra n s ­ m e m b ra n e – He te ro d im e rs c o ns is ting o f α a nd β c h a ins – C o nne c te d to c y to s ke le to n Hemidesmosomes (half desmosomes) • Mediate interactions between keratins, basal membrane, and ECM • Instead of cadherins, Hemidesmosomes interact with the ECM via integrins and strange membraneanchored collagen • • • • • • Ke ra tins 5 a nd 1 4 P le c tin Inte g rin a 6 b 4 C o lla g e n X VII La m in in 5 C o lla g e n typ e VII Epidermolysis bullosa H e m id e s m o s o m e a nd Ep id e rm o lys is b ullo s a • Ke ra tin s ­ EB s im p le x • P le c tin ­ EB s im p le x with M. Dys tro p h y • Inte g rin α6 β4 ­EB jun c tio na l • T yp e X VII c o lla g e n­ EB b e n ig n a tro p h ic junc tio n a l • La m in in 5 ­ EB He rlitz jun c tio na l • T yp e VII c o lla g e n­ EB d ys tro p h ic E p ith e lia l C O MMUNIC AT ING Junc tio ns • G a p Junc tio ns (Ne xus ) Gap Junctions • Clusters of cylindrical hydrophilic channels that allow direct communication between neighboring cells • Allow passage of small molecules (<1000 MW) such as metabolic intermediates and second messengers • High intracellular concentrations of Ca++ close gap junctions Gap junction­mediated communication •The "barrel" through one membrane aligns with barrel in the membrane of the adjacent cell, to form a channel. •An individual junction is formed by 12 copies of connexin (six per membrane) Gap junctions • C o nne xins c a n fo rm h o m o typ ic o r h e te ro ty p ic junc tio ns , wh ic h c h a ng e s th e p e rm e a b ility p ro p e rtie s • Hig h c o nc e ntra tio ns o f C a ++ c lo s e g a p junc tio ns Genetic diseases mapped to connexins • C x3 2 ­ X ­lin ke d C h a rc o t Ma rie n e uro p a th y • C x2 6 ­ S e n s o rin e ura l h e a ring lo s s / ke ra to d e rm a • C x3 1 ­ S e ns o rin e ura l h e a ring lo s s • C x3 0 .3 ­ Do m in a nt s kin d is e a s e (e rth o ke ra to d e rm a ) • C x3 0 ­ Do m ina nt h e a rin g lo s s • C x4 6 a n d C x5 0 ­ Zo nula r p u lve ra n t c a ta ra c t E p ith e lium • An epithelium is comprised of cells which are linked together both mechanically and functionally by close adhesion. ...
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This note was uploaded on 01/04/2012 for the course ANT 610C taught by Professor Johnaris during the Spring '10 term at University of Florida.

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