Cell adhesion adherens

Question 1

What are adherens junctions?

Answer 1

Mediate cell:cell adhesion.
Found in simple and stratified epithelia.
Anchor actin microfilament to membrane.

Question 2

What are adherens junctions made from?

Answer 2

Classical cadherin - single pass transmembrane protein, interacts in space between cells.
B-catenin or replaced by plakoglobin
A-catenin - links complex to actin cytoskeleton.

Question 3

What are classical cadherins?

Answer 3

E-cadherin - epithelia
N-cadherin - neurones, heart, fibroblast
P-cadherin - placenta, epidermis, breast
VE-cadherin - endothelial cells.
Deletion of E, N and VE are lethal.

Question 4

What is morphogenesis?

Answer 4

The process where anatomical structures are generated and organised.
Appearance and disappearance of cadherins drives morphogeneis.

Question 5

What is neurulation?

Answer 5

A type of morphogenesis.
Formation of the neural tube during embryogenesis.
The neural tube goes on to form the spinal cord and the brain.

Question 6

What is the first stage of neurulation?

Answer 6

Epithelial cells of the embryonic ectoderm lose expression of E-cadherin and gain N-cadherin.
As the cadherins change the cells segregate from one another, the ectoderm invaginates and pinches off to form a tube.

Question 7

What is the second stage of neurulation?

Answer 7

The cells that are part of the neural tube lose expression of N-cadherin and gain expression of cadherin-7 - this holds the migrating cells together as loosely associated cell groups.
This allows the cells to break away to form the neural crest.
Neural crest cells then migrate away from the neural tube.

Question 8

What is the third stage of neurulation?

Answer 8

Two groups of migrating cells re-express N-cadherin.
This allows them to aggregate and then differentiate to form peripheral ganglia.

Question 9

How does cadherin adhesiveness change?

Answer 9

Neurulation and the formation of peripheral ganglia is because cadherins are differentially adhesive.
E-cadherin - very adhesive
N-cadherin - less adhesive
Cadherin-7 - least adhesive.

Question 10

What is Epithelial Mesenchymal Transition?

Answer 10

EMT is the process where epithelial cells lose their normal characteristics - adhesive, non-motile - and gain new characteristics - non-adhesive, motile.
e.g. when neural crest cells are able to break away from the neural tube and migrate.

Question 11

What does a loss of E-cadherin cause?

Answer 11

A common event in cancer.
Loss of E-cadherin expression and therefore reduced cell adhesion can result in an EMT, which leads to:
Loss of histological structure
Increased motility
Increased invasiveness

Question 12

How does loss of E-cadherin change tissues?

Answer 12

Normal: tight cell:cell adhesion, well organised structure, non-motile, non-invasive.
Cancer: Loose cell:cell adhesion, disorganised structure, motile, invasive.

Question 13

How does loss of E-cadherin promote cancer?

Answer 13

Loss of E-cadherin mediated cell:cell adhesion allows invasion of the underlying connective tissue.
Tumour cells are then able to enter the bloodstream by crossing the wall of the blood vessel.
They then exit elsewhere and grow at a new site.

Question 14

How can a loss of E-cadherin occur in cancer?

Answer 14

Mutation - inherited mutations in CDH1, predisposes to gastric and breast cancer.
Promoter hypermethylation - downregulation of mRNA - breast, prostate cancer.
Transcriptional silencing - from abberant expression of transcriptional repressors of CDH1.

Question 15

What are focal adhesions?

Answer 15

Mediate cell:matrix adhesion.
Found in epithelial - keratinocyte, and non-epithelial - fibroblast, cells.
Anchor actin microfilaments to the membrane.

Question 16

What are the components of focal adhesions?

Answer 16

Integrins - 2 molecules, a and b chain.
Structural proteins - talin, paxillin
Signalling proteins e.g. focal adhesion kinase

Question 17

How are different integrins expressed?

Answer 17

a5, B1 - bind to fibronectin, ubiquitous (all cells)
a6, B1 - bind to laminin - ubiquitous
a7, B1 - binds to laminin - muscle
a11, B3 - fibrinogen - platelets.
a6, B4 - laminin - hemidesmosomes.

Question 18

What are the conformations of integrin?

Answer 18

Inactive conformation - a and b chains are tightly folded.
Active conformation - chain unfolds into an extended conformation.

Question 19

How do integrins switch between inactive and active conformations?

Answer 19

Triggered by:
Binding to ligand (ECM protein) - outside-in signalling, this increases the affinity of the cytoplasmic tail for Talin.
Binding to talin - inside-out signalling, this increases the affinity of the extracellular domain for matrix proteins.

Question 20

How are actin microfilaments joined to focal adhesions?

Answer 20

During cell migration new actin microfilaments are formed at the leading edge of the cell - the lamellipodium.
These are then incorporated into Focal adhesions, which anchor the lamellipodium to the underlying substratum.

Question 21

What is the protrusion stage of focal adhesions in cell migration?

Answer 21

Actin polymerisation at the leading edge pushes out a lamellipodium.

Question 22

What is the attachment phase of cell migration?

Answer 22

Integrins in the membrane of the leading edge engage ECM proteins.
These then switch their active conformation, recruit Talin, and new focal adhesions are assembled.
The focal adhesions incorporate actin filaments and attach the lamellipodium to the substratum.
This creates traction at the front of the cell.

Question 23

What is the detachment phase of cell migration?

Answer 23

Stretching of the actin cortex creates tension which is relieved when focal adhesions at the back of the cell are degraded and the back of the cell moves forwards.

Question 24

What is an example of inside-out signalling?

Answer 24

Platelets express a11 B3 integrin in an inactive state.
When platelets meet thrombin, talin is activated and activates the integrin.
This increases the affinity of the integrin for fibrinogen (in wound) and leads to formation of a platelet plug at the site of the injury.

Question 25

What is Glanzmann’s disease?

Answer 25

Mutations in a11 or B3 integrin chains prevents the interaction of platelets with fibrinogen at the site of blood clots.
This causes defective clotting and excessive bleeding.