Junctions - 2008 Aris

8/8/2019 Junctions - 2008 Aris

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Medical Cell and Tissue BiologyBMS 6110C

John P. Aris, PhD

Rm B1-8, 392-1873, [email protected]

Ross & Pawlina, 5th Edition, Chapter 5

Cell Junctions


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Cell Junctions

Anchoring - mediate cell-cell and cell-matrix adhesions;linked to cytoskeleton to transmit and distribute stress

Occluding - form seals between epithelial cells; block orregulate (paracellular) permeability between cells

Channel-forming - allow diffusion of small molecules

Signal-relaying - ligands on or released from cell transmit

signals to receptors on adjacent cell (e.g., synapses)


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Cell Junctions in Epithelia

Junctions perform multiple functions in epithelia

MBoC5 Fig 19-3


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Cell Junctions

Cell-cellSymmetrical - same proteins on different cells interact

Tight junction

Zonula adherens

Desmosome

Gap junctions

Cell-matrix

Asymmetrical - cell proteins interact with matrix

Hemidesmosome

Focal adhesion (actin-linked cell-matrix adhesion)


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Cell Adhesion Molecules

Transmembrane proteins with elaborate extracellulardomains that mediate cell-cell or cell-matrix adhesions

Intracellular domains may bind adaptor proteincomplexes that bind and regulate attachment to the

cytoskeleton Attachment to cytoskeleton distributes mechanical stress

Number and activity are regulated (e.g., cells can "let go")

Junctional - proteins clustered into specific structures

Non-junctional - proteins distributed in plasma membrane

Anchoring junction proteins

Calcium dependent - cadherins and selectinsCalcium inde endent - I famil CAMs and inte rins


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Tight Junctions

Occluding junction (encircles epithelial cells) Barrier to diffusion between cells (paracellular pathway) Separates apical and basolateral plasma membranes

Ross Fig 5-12


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Tight Junctions

Tight junction blocks diffusion of soluble tracer molecules

added to either the apical or basolateral compartment

MBoC5 Fig 19-24


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Tight Junction

TEM: TJ is closest to apical surface in epithelium

Freeze fracture of TJ reveals ridges in membranes thatcorrespond to sites of contact between cells

Ridges are linear arrays of occludin and claudin proteins

Ross Fig 5-10


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Tight Junction Permeability

Some claudins and occludins have pores (A, B, and C) thatallow selective (paracellular) movement of ions or solutes

Hereditary hypomagnesemia results from mutated claudin

proteins that fail to resorb of Mg++ across renal epithelia

Side view Top view


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Tight Junction Proteins

Occludins and claudins are transmembrane proteinsthat interact across the intercellular space to form TJs

ZO (zonula occludens) proteins 1-3 link occludin andclaudin to each other, to JAMs, and to actin filaments

JAMs - Ig family adhesion molecules (CAMs) in TJs

Ross Fig 5-11


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Immunoglobulin

(Ig) CAMs

Diverse adhesion functions, all calcium independent Single transmembrane domain glycoproteins Extracellular immunoglobulin (Ig)-like domain(s) NCAM (neural), ICAM (intercellular), VCAM (vascular)


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Zonula

Adherens Anchoring junction

(encircles the cell)

AKA adhesion belt,belt junction, orbelt desmosome

Located "under"tight junction inepithelial cells

Connected to actinmicrofilaments that

join terminal web

MCB6 Fig 19-9


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Zonula Adherens

Cadherin proteins attach to crosslinked actin filaments

Mechanical support - ZA and actin filaments transmit and

distribute stress throughout cell and to neighboring cells

Ross Fig 5-14


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Cadherins

Calcium-dependent cell adhesion molecule Single transmembrane domain glycoproteins

Extracellular domain binds Ca++ and associates withextracellular domains of cadherins on adjacent cells

(homotypic binding interactions) Cytoplasmic domain associates with cytoskeleton

Many cadherins (>40) with tissue-specific distribution:E-cadherin (epithelial)N-cadherin (neural)P-cadherin (placenta)

Important in embryogenesis and cell differentiation

Often misregulated in disease (e.g., cancer)


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Cadherins and Calcium

Calcium binding causes extracellular domains of cadherins

to adopt extended conformation capable of interacting

MBoC5 Fig 19-9


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Cadherins and

Cytoskeleton Catenins are adaptor proteins

that form links to cytoskeleton

Catenins also regulate theadhesiveness of cadherins

F-catenin complex links classiccadherins to actin filaments

(e.g., in zonula adherens) K-catenin (plakoglobin)

complex links non-classicalcadherins to intermediate

filaments (e.g., in desmosome)

MBoC5Fig 19-14


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Desmosomes

Anchoring junctions

AKA macula adherens

Function as "spot

welds" to join cells Located along lateral

plasma membranes ofcolumnar epithelialcells or on processesof squamous cells

Intermediate filamentsassociate with plaqueproteins in cytoplasm


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Desmosomes


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Desmosomes

Non-classical cadherins interact across intercellular space Adaptor proteins form a dense plaque that interconnects

cadherins and binds them to intermediate filaments

MBoC5 Fig 19-17


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Desmosomes

Desmoglein and desmocollin are non-classical cadherins

Adaptor proteins such as K-catenin (plakoglobin) and

desmoplakin link cadherins to intermediate filaments

MBoC5 Fig 19-17


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Gap

Junction

Channel-forming junction

Named for gap of regularwidth between cellsvisualized by TEM

Water-filled junctionstransport molecules


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Connexin - protein subunit, six form a hexameric connexon Connexons - two align to form the gap junction channel Regulation - elevated calcium concentrations close channel

Ross Fig 5-17 Gap

Junction


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Hemidesmosomes

Hemidesmosome - "half-desmosome" in appearance only Mediates attachment to basal lamina (extracellular matrix) Cytoplasmic plaque is attached to cytoskeletal elements

Ross Fig 5-31


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Hemidesmosomes

Integrins - membrane protein that "integrates" cell into matrix

Ross Fig 5-31


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Integrins

Mediate calcium-independent cell-matrix adhesion Function as dimers of two membrane proteins (E and F) Adaptor proteins link integrins to intermediate filaments in

hemidesmosomes or actin filaments in focal adhesions Integrins bind matrix proteins such as laminin or fibronectin

MBoC5 Fig 19-45


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Focal Adhesions

Anchoring junction (AKA actin-linked cell-matrix adhesion) Growing fibroblasts form many focal adhesions (orange)

that serve as anchoring points for actin filaments (green)

See Ross Fig 5-30


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Focal

Adhesions

Fibroblasts attach to extracellular matrix via focal adhesions

Integrins - membrane proteins link actin filaments and matrix

Ross Fig 5-30


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Selectins

Calcium-dependent

Single transmembranedomain glycoprotein

Extracellular domain binds

carbohydrates (classified aslectins - proteins that bindcarbohydrates)

Lectin domain binds specific

sugars on protein or lipid Three major classes:

P-selectins (platelets)E-selectins (endothelial cells)

L-selectins (leukocytes)


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Transepithelial extravasation is associated with inflammation

Regulated by P-selectin exocytosis and integrin activation

Extravasation

MCB6Fig 19-36


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Adhesion Protein Interactions


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Adhesion Protein Interactions

Cis interactions - between proteins on the same cell Trans interactions - between proteins on different cells

Combination of interactions promotes junction formation


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Junction Proteins

JunctionMembrane

proteins

Cytosolic

proteinsCytoskeleton

TightOccludins,claudins

ZO proteinsActin

filaments

Zonula

adherens

Cadherins

(classical)

Catenins (EF),

vinculin, Eactinin

Actin

filaments

DesmosomeCadherins:desmocollindesmoglein

Desmoplakin,plakoglobin(K-catenin)

Intermediatefilaments

Focaladhesions

IntegrinsVinculin, talin,

E-actininActin

microfilaments

Hemi-

desmosomeIntegrins Plectin, BP230

Intermediate

filaments


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Blistering Disease

Many mechanisms underlie blistering disorders of the skin

Pemphigus group - autoimmune disease in whichautoantibodies target desmogleins present in desmosomes


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Pemphigus Histology

Acantholysis - separation of epidermal keratinocytes (H&E)

Junctions - 2008 Aris

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