Lecture 12 - Epithelial cell polarity Flashcards
What is polarity in epithelia?
A difference in structure, composition or function between the two poles of a cell, such as apical/basolateral in an epithelial cell.
Also refers to location of a
protein in either apical or basolateral membranes
Why must proteins be sorted and directed to apical and basolateral membranes during epithelial cell development?
For the ion transport pathways that allow epithelial cells to function - Essential for epithelia to transport ions/molecules
What is the formation of the cell-basement membrane and cell-cell interactions necessary in?
Establishing epithelial cell polarity
What are associated with first cell-cell interaction/what initiates epithelia formation?
adherens junction
What proteins are involved in the formation of AJs?
Nectin proteins
E-cadherin
Catenins
What is the role of nectin proteins in AJ formation?
Nectin proteins make initial cell-cell contact. Nectins on neighbouring cells interact.
- Ca2+-independent cell adhesion.
What is the role of E-cadherin proteins in AJ formation?
E-cadherin on one cell forms homodimer with E-cadherin on neighbouring cell
- requires Ca2+
Cytoplasmic tail binds to catenins
What is the role of catenins proteins in AJ formation?
Link actin of e-cadherin to cytoskeleton
Catenins also link nectin and cadherin complexes to pull all the proteins together to make the AJ.
What is the generalised function of catenins?
Catenins - connective/glue to link things together
What do TJ components interact with?
TJ components interact with apical polarity protein complexes
What polarity complexes are activated during the formation of TJs/epithelial polarity
PAR
CRB
SCRIB
What happens when small GTP binding proteins are activated during the formation of TJs/epithelial polarity?
Small GTP binding protein activated - cdc42
Activates aPKC
how are polarity complexes activated during the formation of TJs/epithelial polarity?
aPKC
What are the role of polarity complexes in epithelial polarity?
Maintenance of polarity
Where are the three scaffolding protein polarity complexes located?
- formation of epithelial polarity
- PAR complex – apical, near TJ
- CRB complex – apical, near TJ
- SCRIB complex – basolateral
What are the four domains responsible for establishing polarity?
PAR complex
CRB complex
SCRIB complex
aPKC
What is aPKC?
aPKC is an atypical protein kinase C that is activated by small GTP binding proteins (cdc42).
aPKC is the only polarity protein that has enzymatic activity
aPKC interacts with and phosphorylates the CRB and SCRIB complexes.
What happens when CRB and SCRIB are phosphorylated?
When phosphorylated, the polarity complexes are correctly locate themselves in either the apical or basolateral domain.
What does mutual exclusion refer to?
How polarity complexes (or other proteins) are located in only one epithelial domain (apical or basolateral)
Summarise the formation of TJs and epithelial polarity (7 steps)
- Interactions between neighbouring cells, and between cells and basement membrane.
- Interaction between cells forms adherens junction.
- Small GTP proteins (cdc42) activated.
- Cdc42 activates aPKC - a polarity complex protein.
- Tight junctions start to form.
- Positioning of PAR and CRB polarity complexes to apical domain, and SCRIB complex to basolateral domain.
- Apical-basolateral polarity established.
What happens to polarity complexes for cell division or cell removal?
They are pulled apart and the are reformed
What is the main ligand for the removal of protein complexes?
TGF-B
What are the two pathways of TGF-B in the removal of protein complexes?
Activation of SMAD proteins (transcription proteins)
Downregulation of PAR complex
- both result in Epithelial-mesenchymal transition
Describe the TGF-B SMAD protein pathway
TGF-B will bind to receptor which activates SMAD2/3. SMAD2/3 is a transciption factor process which goes into nucleus to cause upregulation of the genes that becomes proteins that can disrupt (down regulate) the tight junctions via inhibition
What can mutations in polarity complex proteins cause?
• Decreased formation or lack of tight junctions so barrier, gate and fence functions compromised.
• Changes in cell-cell adhesion and cell movement.
• Changes in location of apical and basolateral proteins.
• Cancer
Normal epithelial physiology
High cell density – ZO1 keeps transcription factors that promote cell division localised to TJs preventing cell division. Epithelia carries out regular functions e.g. absorption/secretion.
What is the pathophysiology for wound healing/damage to epithelia?
Low cell density –transcription factors that promote cell division move from TJs to nucleus to stimulate cell division (sensing a gap in the epithelia that needs to be filled with new cells to repair junctions and maintain polarity).
What is the pathophysiology of cancer in epithelia?
Genetic changes in cancer cells of epithelia may promote EMT: cell division increases and loss of epithelial polarity.
