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can exchange signals that coordinate their behavior and can regulate their
pattern of gene expression
• epithelial tissue (depends on cytoskeleto of the cells, linked from cell to cell by anchoring junctions)
Cell junctions – diverse in structure and with multiple assignments
The protein E-cadherin is importen in embryo development, making the embryo cells stick
together. Mutations in E-cadherin is embryo lethal.
Cadherin superfamily
Binding occurs at the N-terminal end, the end that lies away from the membrane.
Cadherin
Cadherins bind with low affinity, but the formation of many weak bonds in parallel give a
strong attachment afterall.
Making and breaking of anchoring junctions is important for the constant turnover of tissues!
Cadherin – selective cell-cell adhesion
Cadherins are not like any glue, they mediate highly selective recognition.
Cells from amphibian embryos dissociated, mixed, and then allowed to reassociate. Mesoderm cells
(green), neural plate cells (blue) and epidermal cells (red) sort out in a normal arrangement.
Cells depend on guidance from tissue along the path of ”movement”, involving;
• chemotaxis
• chemorepulsion movement under the influence of chemicals that attract or repel migrating cells
• contact guidance migrating cells touch other cells or extracellular matrix components, making transient
adhesion that govern the selected track.
In the processes of sorting out, contact guidance and tissue assembly cadherins
play a crucial part!
Cadherin – involved in epithelial-mesenchymal transitions
Assembly of cells into an epithelium is a reversible process.
With active adhesion molecules, mesenchymal cells (dispersed unattached cells) can come together and
form an epithelium.
An epithelium can also disperse and migrate away as separate cells.
A control system seems to be critical for EMT, consisting of the following gene regelatory components:
• Slug
• Snail
• Twist
These three have E-cadherin as a downstream component.
EMT also occur during cancer. Mutations that disrupt the production of E-cadherin are found in
cancer cells, and are thought to help make them malignant.
• The components vary according to type of anchorage, but in general you will
find beta-catenin and/or gamma-catenin to play a central part
• In adherens junctions, you will also find a remote catenin relative – p120-catenin
Adhesion junctions
1. In nonepithelial tissue they are small 2. In epithelial cell they form an adhesion
punctate attachments, indirectly belt close beneath the apical face of the
connecting cortical actin filaments of epithelium
to interacting cells
The bundles of intermediate filaments that are anchored to the desmosome have a
great tensile strenght. What kind of intermediate filament anchored to the desmosome
depend on the cell type (keratine in epithelial cells, desmin in heart muscle cells..)
Selectins
One of three other superfamilies (integrins, selectins and Ig), in addition to the cadherins, that is
central in cell-cell adhesion
Three types;
1) L- selectin (on white blood cells)
2) P- selectin (blood platelets/endothelial cells)
3) E- selectin (on activated endothelial cells)
The selectins control the binding of white blood cells to the endothelial cells lining
blood vessels.
There they can ”help” the blood cells migrating out of the bloodstream and into the
tissue ( in collaboration with integrin)
Especially the nervous system rely on complex systems of adhesion molecules ( in addition to chemotaxis/signal
factors) guide axon outgrowth, and thereby specific nerve connections
The scaffold molecules can also bind to eachother, and make up a mat of proteins needed in the synapse
• and they are ”free” on the other side – the apical side
This require that neighboring cells are sealed together, so that molecules can not leak freely across
the cell sheet
Occluding junctions are called thight junctions, and play and important role in
transcellular transport
• Thight junctions are impermeable to macromolecules, but the permeability to small molecules
varies. Thight junctions in the small intestine have a different permeability ”pattern” than
thight junctions in the epithelium of the urinary bladder.
Thight junctions can perform paracellular transport,meaning that cells can transiently
alter their juctions.
This is important in absorptions of aa and monosaccharides from the lumen after a meal,
when concentration is high enough to allow passive tranport
Thight junctions
Thight junctions consist of a branching network of sealing strands.
The sealing strands encircles the apical end of each cell in the epithelial cell sheet
Apex
Crumbs
Par3
Rac complex
Par6
Cdc42
aPKC
Basal
Scribble
complex
The cytoskeleton + Rac directs delivery of basal lamina components to the opposite end of the cell
Planar cell polarity
• gap junctions are present in most animal tissue (both connective tissue and epithelia)
• the gap is spanned by channel-forming proteins
• allows both inorganic ions and water-soluble molecules to pass
• connect cells both eletrically and metabolically
• coupled cells share small molecules, but not macromolecules
Gap junctions
1. connexins 2. innexins
Multi-tasking
Collagen XVIII
Figure showing the subunits of laminin. The yellow boxes are the binding sites for different
molecules !
Laminin is essential to basal lamina assembly and the anchoring to cells!
INTEGRINS AND CELL-MATRIX ADHESION
Matrix receptors tie the matrix outside the cell to the cytoskeleton inside the cell.
Several types of molecules can function as matrix receptors, but the most important one is
INTEGRIN
• integrins can transmit signals in both directions across the cell membrane
• integrins ”grab” intracellular and extracellular structures, and loss of tension make molecular signalling
complexes to fall aparton either side of the membrane
• integrins can transmit mechanical and molecular signals
• integrins can convert one type of signal into the other
• talin competes with integrin alfa chain for its binding site on the beta chain
• upon talin binding to beta-chain, the alfa-beta linkage is broken and the two integrin legs can spring apart
• this also drives the integrin into an active conformation INSIDE-OUT ACTIVATION
• this activation is triggered by intracellular regulatory molecules, such as PIP2 (phosphinositide
PIP2 (and others) is produced in response to outside signals transmitted through cell-
surface receptors (G-coupled receptors, tyrosine kinase receptors)
Integrin
Integrins usually bind their ligand with low affinity, and strong adhesion depends on
clustering of integrins. This is the case in i.e. hemidesmosomes.
Src family
Phosphotyrosine
Clustered FAK molecules of cytoplasmic tyrosine
docking site kinases Outside-in signaling form integrins, via
Cross-phosphorylate eachother FAK and Src-family kinases, is relayed
into the cell
In connective tissues the extracellular matrix is ”larger” than the cells it surrounds.
It determines the tissue`s physical properties.
• survival
• development
• migration
• proliferation
• shape
• function
Fibroblasts
- Chondroblasts (cartilage)
- osteoblasts (bone)
Main GAGs:!
1. hyaluronan!
2. chondroitin sulfate / dermatan sulfate!
3. heparan sulfate!
4. keratan sulfate!
GAG
Core protein
Assembled in the Golgi Delivery to the cell by exocytosis
Polypeptide chain
of mebrane-bond
• linkage tetrasaccharide serve ribosomes
as a primer for polysaccharide
growth
• polarized sugars are covalently
modified
- Proteglycans have an important role in chemical signalling (bind secreted signal molecules)
Collagen fibrils
produced by
fibroblasts
Collagen
Collagen undergo post-translational modifications
Collagen
After secretion, procollagen is converted into collagen molecules. Collagen molecules assemble into
collagen fibrils.
• The fibrils are strenghtened by formation of covalent cross-links between lysine residues
It is the connective tissue itself that determine the size and arrangement of
collagen fibrils by gene regulation!
Elastin