Cell Adhesion

Question 1

Adhesion of cells to each other and their extracellular matrix provides many of the cues neccessary for controlling:

Answer 1

• Cell migration
• Cell shape
• Survival
• Proliferation
• Differentiation

Question 2

These events regulate an organism’s normal development, maintenance, and recovery from injury and infection.

Defects in the pathways associated with cell adhesion provide the basis for:

Answer 2

• Cell transformation
• Cancer cell metastasis
• Developmental defects
• Cardiovascular disease

Question 3

Protein complexes forming at specific sites of cell membranes (typically epithelium)

Answer 3

cellular junctions

Question 4

cellular junctions organize contacts of cells with one another through:

Answer 4

• Adhesion
• Definition of cellular domains
• Control of permeability of epithelium
• Intracellular signaling
• Intercellular communication / signal transmission

Question 5

Cellular junctions organize contact between cells and extracellular matrix:

Answer 5

• Anchoring
• Intracellular signaling

Question 6

Typical components (cellular junctions)

Answer 6

• Transmembrane adhesive protein
• Cytoplasmic adapter (anchor) protein
• Cytoskeletal filament

Question 7

Arrangement (cellular junctions)

Answer 7

• Macula: patch-like junction of limited extent
• Zonula: junction which encircles the entire cell

Question 8

Junctional combinations

Answer 8

• Junctional complex (terminal bar): cuboidal or columnar epithelium
• Intercalated disc: cardiac muscle

Question 9

Typical three-component arrangement

Answer 9

Question 10

Types of junctions

Answer 10

1. Gap (Nexus) junction (communicating junction)
2. Tight junction (occluding junction, zonula occludens)
3. Adherens junctions
   
   1. Cells attaching to other cells
      
      1. Adherens junction (or zonula adherens, intermediate junction)
      2. Desmosome (macula adherens)
   2. Cells attaching to / anchoring in the extracellular matrix
      
      1. Hemidesmosome
      2. Focal adhesion

Question 11

Three (Four) functional classes of cell junctions in animal tissues

Answer 11

1. Anchoring junctions
   
   1. Adherens Junctions
2. Occluding Junctions
   
   1. Tight Junctions
3. Channel-forming Junctions
   
   1. Gap Junctions
4. Signal-relaying junctions

Question 12

Summary figure of cell adhesion proteins

Answer 12

Question 13

Gap/Nexus/Communicating junction

Answer 13

• Plaque-like junction
• Cell membranes of neighboring cells very close together; intercellular space only 2-3 nm
• Can be found in all basic tissue types
• Common in epithelial cells, smooth and cardiac muscle cells, neuronal cells, and osteocytes

Question 14

Integral membrane protein

Answer 14

connexin

6 connexins form connexon (connexin hemichannel)

Connexon has central channel (diameter 2nm)

Connexons of one cell connect to connexons in adjacent cell to form hydrophilic channel

Tens to hundreds of aligned connexon pairs hexagonally packed in gap junction

Aqueous channel formed between cytoplasm of adjacent cells

Passage of small signaling molecules and ions possible

Connected cells are electrically coupled for coordinated responses to stimuli

Different members of connexin family result in differences in permeability

Question 15

Connexin mutations are linked to:

Answer 15

• deafness
• cataracts
• Charcot-Marie-Tooth demyelinating disease
• oculodentaldigital dysplasia

Question 16

Tight/occluding junction

Answer 16

Anastomosing strands of adhesive transmembrane proteins

Linear series of contacts to proteins of adjacent cell

Intercellular space obliterated at contact site

Junction encircles entire cell

Found close to the apical end of cuboidal or columnar epithelial cells

Question 17

Transmembrane proteins (tight/occluding junction):

Answer 17

• members of claudin family (4 pass membrane proteins)
• occludin
• junctional adhesive

Transmembrane adhesive proteins interact homotypically with proteins in adjacent cell

Question 18

Some cytoplasmic proteins (tight/occluding junction):

Answer 18

• kinases
• transcription factors
• cell polarity-related proteins

Actin filaments associated

Question 19

Tight/occluding junction:

Movement of ions and small molecules in intercellular space:

Tightness (permeability):

Movement of membrane proteins:

Answer 19

Movement of ions and small molecules in intercellular space prevented / controlled

Tightness (permeability) depends on number of junctional strands, their completeness, and type of adhesive protein

Movement of membrane proteins limited

Question 20

Adherens junctions

Cells held together or attached to/anchored in the:

Intercellular space between attached cells:

Adhesive junctions commonly involved in:

Loss of contact to adjacent cells or extracellular matrix may trigger:

Answer 20

Cells held together or attached to / anchored in the extracellular matrix

Intercellular space between attached cells: 20 nm wide at location of adhesive junction

Adhesive junctions commonly involved in (intra) cellular signaling (e.g. for nuclear transcription, tumor suppression, differentiation)

Loss of contact to adjacent cells or extracellular matrix may trigger apoptosis or result in loss of polarity

Question 21

Cell-to-cell adhesive junctions:

Cell-to-ECM adhesive junctions:

Answer 21

• Cell-to-cell adhesive junctions:
  
  • Transmembrane adhesive proteins members of cadherin (calcium ion-dependent proteins) family
  • Cytoplasmic adapter proteins members of the catenin family
• Cell-to-ECM adhesive junctions:
  
  • Similar to cell-to-cell adhesive junctions, but:
  • Transmembrane proteins members of integrin family (heterodimers with alpha and beta subunits)

Question 22

Adhesive junction with electron-lucent intercellular space and ___________on cytoplasmic face

Associated with ____________

Answer 22

Adhesive junction with electron-lucent intercellular space and ‘fuzzy’ plaque on cytoplasmic face

Associated with belt-like band of actin

Encircles entire cell (zonula)

Found basal to tight junction zonula in epithelial cells

Question 23

• Transmembrane adhesive proteins (Adherens junction):
• Cytoplasmic adapter proteins:
  
  • Interact with:
• Cytoskeletal element:

Answer 23

• Transmembrane adhesive proteins: E-cadherin; (nectin)
• Cytoplasmic adapter proteins: a- and b-catenin; (p120 catenin, afadin, vinculin, a-actinin)
  
  • Catenins interact with cytoplasmic domain of trans-membrane protein, cytoskeletal proteins, and other cytoplasmic proteins
• Cytoskeletal element: actin filaments (continuous with apical terminal web)

Question 24

Adheren junction functions:

Answer 24

• Contribution to adhesive force between one cell and another
• Support to apical domain of epithelial cell
• Intracellular signaling

Question 25

Desmosome

Answer 25

* Disk-shaped adhesive junction (macula) * Electron-dense cytoplasmic attachment plaque * Intercellular space (ca. 30 nm; somewhat wider than in ZA) filled with highly-ordered proteins * Found basal to zonula adherens in epithelial cells in band encircling cell as well as scattered over lateral cell surface * Common in many tissue types

Question 26

Transmembrane adhesive proteins (cadherins) - Desmosome: Cytoplasmic adapter proteins (catenin): Cytoskeletal element:

Answer 26

* Transmembrane adhesive proteins (cadherins): desmoglein, desmocollin * Interaction of cadherins from adjacent cells results in electron-dense line in intercellular space * Cytoplasmic adapter proteins (catenin): desmoplakin, plakoglobin, plakophilin * Cytoskeletal element: intermediate filaments (anchoring in catenin plaque); type depends on tissue type

Question 27

Autoimmunity to Desmosomes (Cadherins)

Answer 27

Pemphigus Vulgaris ## Footnote Intra-oral view showing several lesions occurring predominantly on the buccal gingiva and appearing as small white pustules and a few ulcerated areas associated with gingival growth. 1B) Full mucosal healing after high-dose systemic corticosteroid treatment. 1C) Histopathological sections revealing well-defined foci of suprabasal acantholysis with crusting and a few neutrophils in the overlying space with mixed lymphocytes and eosinophils. 1D) Direct immunofluorescence showing bright intercellular deposition of IgG and C3 in the epidermis.

Question 28

Linked to mutations in Desmosome Proteins

Answer 28

Epidermolysis Bullosa

Question 29

Junctional Combinations 1. Epithelial Junctional complex Symmetrical structures formed between adjacent cells and consist of three components:

Answer 29

1. a band of tight junctions (TJ), forming an occluding zone in the top position 2. a band of anchoring junctions in the middle position (zonula adherens, ZA) 3. a circle of spot desmosomes (DES) in the bottom position (macula adherens)

Question 30

Junctional combinations Intercalated disc:

Answer 30

*

Question 31

Junctional combinations Intercalated disc:

Answer 31

* Fascia adherens * desmosomes * gap junctions

Question 32

Adhesion to basement membrane (basal lamina):

Answer 32

* Sheet-like arrangement of extracellular matrix proteins ( ca. 20-100 nm wide) * Binds epithelium to underlying connective tissue * Also found around muscle cells and nerve fibers * Provides metabolic support * Filters material (barrier function) * Controls epithelial growth and differentiation; prevents downward epithelial growth

Question 33

Basement membrane (Basal lamina) Components: Layers (visible only in TEM):

Answer 33

* Components: * Heparan sulfate (glycosamino-glycan) * Collagen type IV * Fibronectin * Laminin * Entactin * Collagen type III * Collagen type VII (anchoring fibrils) * Layers (visible only in TEM): * Lamina lucida * Lamina densa * Lamina fibroreticularis

Question 34

Hemidesmosome

Answer 34

* Provides tight anchoring of epithelial cell to basal lamina and underlying connective tissue * Plaque-like adhesive junction morphologically similar to a half-desmosome * Forms at the basal side of certain epithelial cells in zone of contact with basal lamina

Question 35

* Transmembrane adhesive proteins (hemidesmosome): * Binds to: * Cytoplasmic adapter proteins: * form: * Cytoskeletal elements:

Answer 35

* Transmembrane adhesive proteins: integrin (a6b4) * Integrins bind to basal lamina glycoprotein laminin * Cytoplasmic adapter proteins: bulbous pemphigoid antigen 230 (BP230); plectin * Cytoplasmic proteins form dense plaque * Cytoskeletal element: intermediate filaments (anchoring in plaque)

Question 36

Focal adhesion

Answer 36

* Dynamic assembly of many (\>50) different proteins * Provides linkage of cell to extracellular matrix * Important for intracellular signaling * Transmembrane adhesive protein: integrin heterodimers * Cytoplasmic adapter proteins: a-actinin, vinculin, talin * Cytoskeletal element: actin filaments * Integrins bind to ECM proteins fibronectin, laminin, collagen

Question 37

Summary Figure

Answer 37

Question 38

Summary Table

Answer 38