Medical Cell and Tissue Biology

BMS 6110C

Cell Junctions
John P. Aris, PhD
Rm B1-8, 392-1873, johnaris@ufl.edu

Ross & Pawlina, 5th Edition, Chapter 5

 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 or
regulate (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)
 Cell Junctions in Epithelia

MBoC5 Fig 19-3

• Junctions perform multiple functions in epithelia

 Cell Junctions
Cell-cell
Symmetrical - 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)
 Cell Adhesion Molecules
• Transmembrane proteins with elaborate extracellular
domains that mediate cell-cell or cell-matrix adhesions
• Intracellular domains may bind adaptor protein complexes
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 selectins
Calcium independent - Ig family (CAMs) and integrins
 Tight Junctions

Ross Fig 5-12

• Occluding junction (encircles epithelial cells)

• Barrier to diffusion between cells (paracellular pathway)
• Separates apical and basolateral plasma membranes
 Tight Junctions
MBoC5 Fig 19-24

• Tight junction blocks diffusion of soluble tracer molecules

added to either the apical or basolateral compartment
 Tight Junction
Ross Fig 5-10

• TEM: TJ is closest to apical surface in epithelium

• Freeze fracture of TJ reveals ridges in membranes that
correspond to sites of contact between cells
• Ridges are linear arrays of occludin and claudin proteins
 Tight Junction Permeability
Side view Top view

• Some claudins and occludins have pores (A, B, and C) that

allow selective (paracellular) movement of ions or solutes
• Hereditary hypomagnesemia results from mutated claudin
proteins that fail to resorb of Mg++ across renal epithelia
 Tight Junction Proteins

Ross Fig 5-11

• Occludins and claudins are transmembrane proteins

that interact across the intercellular space to form TJs
• ZO (zonula occludens) proteins 1-3 link occludin and
claudin to each other, to JAMs, and to actin filaments
• JAMs - Ig family adhesion molecules (CAMs) in TJs
 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)
MCB6 Fig 19-9
Zonula
Adherens
• Anchoring junction
(encircles the cell)
• AKA adhesion belt,
belt junction, or
belt desmosome
• Located "under"
tight junction in
epithelial cells
• Connected to actin
microfilaments that
join terminal web
 Zonula Adherens
Ross Fig 5-14

• Cadherin proteins attach to crosslinked actin filaments

• Mechanical support - ZA and actin filaments transmit and
distribute stress throughout cell and to neighboring cells
 Cadherins
• Calcium-dependent cell adhesion molecule
• Single transmembrane domain glycoproteins
• Extracellular domain binds Ca++ and associates with
extracellular 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)
 Cadherins and Calcium

MBoC5 Fig 19-9

• Calcium binding causes extracellular domains of cadherins

to adopt extended conformation capable of interacting
MBoC5
Fig 19-14 Cadherins and
Cytoskeleton
• Catenins are adaptor proteins
that form links to cytoskeleton
• Catenins also regulate the
adhesiveness of cadherins
• -catenin complex links classic
cadherins to actin filaments
(e.g., in zonula adherens)
• -catenin (plakoglobin)
complex links non-classical
cadherins to intermediate
filaments (e.g., in desmosome)
 Desmosomes
• Anchoring junctions
• AKA macula adherens
• Function as "spot
welds" to join cells
• Located along lateral
plasma membranes of
columnar epithelial
cells or on processes
of squamous cells
• Intermediate filaments
associate with plaque
proteins in cytoplasm
Desmosomes
 Desmosomes

MBoC5 Fig 19-17

• Non-classical cadherins interact across intercellular space

• Adaptor proteins form a dense plaque that interconnects
cadherins and binds them to intermediate filaments
 Desmosomes

MBoC5 Fig 19-17

• Desmoglein and desmocollin are non-classical cadherins

• Adaptor proteins such as -catenin (plakoglobin) and
desmoplakin link cadherins to intermediate filaments
 Gap
Junction

• Channel-forming junction
• Named for gap of regular
width between cells
visualized by TEM
• Water-filled junctions
transport molecules <1
kDal such as ions,
nucleotides (including
cAMP), and metabolites
Ross Fig 5-17
Ross Fig 5-17
Gap
Junction

• Connexin - protein subunit, six form a hexameric connexon

• Connexons - two align to form the gap junction channel
• Regulation - elevated calcium concentrations close channel
 Hemidesmosomes

Ross Fig 5-31

• Hemidesmosome - "half-desmosome" in appearance only

• Mediates attachment to basal lamina (extracellular matrix)
• Cytoplasmic plaque is attached to cytoskeletal elements
 Hemidesmosomes
Ross Fig 5-31

• Integrins - membrane protein that "integrates" cell into matrix

 Integrins

MBoC5 Fig 19-45

• Mediate calcium-independent cell-matrix adhesion

• Function as dimers of two membrane proteins ( and )
• Adaptor proteins link integrins to intermediate filaments in
hemidesmosomes or actin filaments in focal adhesions
• Integrins bind matrix proteins such as laminin or fibronectin
 Focal Adhesions

See Ross Fig 5-30

• Anchoring junction (AKA actin-linked cell-matrix adhesion)

• Growing fibroblasts form many focal adhesions (orange)
that serve as anchoring points for actin filaments (green)
 Focal
Adhesions

Ross Fig 5-30

• Fibroblasts attach to extracellular matrix via focal adhesions

• Integrins - membrane proteins link actin filaments and matrix
 Selectins
• Calcium-dependent
• Single transmembrane
domain glycoprotein
• Extracellular domain binds
carbohydrates (classified as
lectins - proteins that bind
carbohydrates)
• Lectin domain binds specific
sugars on protein or lipid
• Three major classes:
P-selectins (platelets)
E-selectins (endothelial cells)
L-selectins (leukocytes)
 Extravasation

MCB6
Fig 19-36

• Transepithelial extravasation is associated with inflammation

• Regulated by P-selectin exocytosis and integrin activation
Adhesion Protein Interactions
 Adhesion Protein Interactions

• Cis interactions - between proteins on the same cell

• Trans interactions - between proteins on different cells
• Combination of interactions promotes junction formation
 Junction Proteins
Membrane Cytosolic
Junction Cytoskeleton
proteins proteins
Occludins, Actin
Tight ZO proteins
claudins filaments

Zonula Cadherins Catenins (), Actin

adherens (classical) vinculin, actinin filaments

Cadherins: Desmoplakin,
Intermediate
Desmosome desmocollin plakoglobin
filaments
desmoglein (-catenin)
Focal Vinculin, talin, Actin
Integrins
adhesions -actinin microfilaments
Hemi- Intermediate
Integrins Plectin, BP230
desmosome filaments
 Blistering Disease

• Many mechanisms underlie blistering disorders of the skin

• Pemphigus group - autoimmune disease in which
autoantibodies target desmogleins present in desmosomes
 Pemphigus Histology

Acantholysis - separation of epidermal keratinocytes (H&E)