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What is the extracellular matrix (ECM)?
The ECM is a substance secreted by cells into their outside environment. It is composed mainly of proteins and complex polysaccharides.
Name the seven functions of the ECM.
- 1. Gives structural support to cells
- 2. Modifies the shape and function of cells
- 3. Provides signals that regulate cell survival
- 4. Regulates the development of cells
- 5. Directs proliferative activity of cells
- 6. Forms adhesive contacts with cells
- 7. Regulates the migration of cells (cells tug and pull on the ECM in order to move)
What are the two types of ECM?
Connective tissue and basement membrane
Name and describe the structure of the two components of connective tissue.
- 1. Ground Substance: jelly-like, amorphous, made up of water, electrolytes, polysaccharides, proteins; the consistency varies in specialized connective tissue (more solid in cartilage, mineralized in bone, liquid in unclotted blood)
- 2. Fibers: mainly composed of two proteins: collagen and elastin
What is the function of ground substance?
- resists compression
- permits diffusion of nutrients and wastes between cells
What is the function of fibers?
To provide structural support
- main ECM protein
- makes up about 25% of protein in body
- flexible, but strong and resistant to stretching
- a polymer composed of repeating units of tropocollagen (each tropocollagen is a helix of three subunits- alpha chains)
- 29 different collagen genes in humans
- main component of structures known as elastic fibers
- very stretchy
- very useful to make flexible, strong materials
Which three types of molecules is ground substance primarily made of?
- glycosaminoglycans (GAGs)
- proteoglycans (PGs)
- glycoproteins (GPs)
a chain of carbohydrates
The process of adding carbohydrates to proteins.
- type of glycans
- negatively charges surfaces attract cations like sodium
- high sodium content attracts fluid which makes the material resistant to compression
- linked to proteins to form proteoglycans
- ie. heparin - anticoagulant
Give an example of the clinical relevance of GAGs.
Failure to break down GAGs causes mucopolysaccharidoses (MPS) diseases ie. dwarfism, mental retardation, cardiomyopathy, etc
What is hyaluronic acid an example of?
- the only GAG that does not bing proteins directly
- good lubricant - found in joints
- many biological and medical roles - wound repair, cell migration, inflammation
Contrast glycoproteins and proteoglycans.
- Glycoproteins are proteins that contain carbohydrate chains.
- Proteoglycans are a type of glycoproteins that are heavily glycosylated (bing to GAG). Glycoproteins are 1-60% carbohydrate by weight and have numerous, short, branched oligosaccharides. Proteoglycans are up to 95% carbohydrate by weight and have mostly long, unbranched GAG chains (can be enormous).
Provide an example each for PGs and GPs.
- PG: Aggracan - major component of cartilage
- GP: Fibronectin - key molecule in blood clotting and tissue repair
Name five types of cells that can be found in the ECM.
- tendon cells
Which cell type sunthesizes and secretes the precursors of all the components of the ECM, including ground substance and collagen fibers?
Define basement membrane.
The interface between epithelium and connective tissue (under light microscopy).
With the high resolution of electron microscopy, the basement membrane appears as two distinct parts. What are they?
- 1. Basal lamina - produced by epithelial cells
- 2. Reticular lamina (aka lamina reticularis) - produced by the connective tissue
What are the functions of the basement membrane?
- mechanical barrier
- anchor (firm and flexible support) for the epithelium
- molecular filter for the epithelium
What is the basal lamina composed of?
- lamina lucida - mainly the GPs laminin and integrins; light portion on a TEM micrograph
- lamina densa - mostly type IV collagen (also the PG perlecan and the GAG Heparan sulfate); dark portion on a TEM micrograph
- lamin binds collagen and integrins and acts as a bridge between the two layers.
What is the reticular lamina made of?
- collagens I and III
- anchoring fibrils (type VII collagen fibers)
- GP Fibrillin
Fill in the blanks.
- Epithelial cell
- lamina lucida
- lamina densa
- basal lamina
- reticular fibers (type III collagen)
- anchoring plaque (type IV collagen)
- anchoring fibrils (type VII collagen)
- lamina reticularis
Give an example of the clinical relevance of the basement membrane.
Mutations in collagen IV (component of anchoring plaques) cause Alport syndrome; may result in kidney failure, hearing loss, cataracts
Name the two types of Cell-ECM adhesion complexes.
- 1. Hemidesmosomes (anchoring junctions)
- 2. Focal Contacts (anchoring junctions)
Describe the general architecture of a cell-ECM junction.
- 1. Cell adhesion molecules - bind to ECM glycoproteins and fibers
- 2. linker/adaptor protein that binds both the adhesion molecules and the cytoskeleton
- 3. Cytoskeletal molecules.
Describe the structure of integrins.
- Integrins are the main ECM adhesion protein in hemidesmosomes and focal contacts.
- Transmembrane proteins
- Two types: alpha and beta integrins
- There are 8 beta and 18 alpha integrins in the human genome.
- A functional integrin is composed of a heterodimer - one alpha and one beta integrin.
- There is a large number of combinations of different heterodimers that can perform specialized functions.
- Cytoplasmic tail recruits many kinds of proteins- assembles an adhesion complex
Explain how integrins can be activated.
- Integrins exist in two states: high affinity and low affinity.
- There are two modes of activation: outside-in and inside-out.
- Outside-in activation involves an ECM ligand binding to low affinity integrin and converting it to high affinity.
- Inside-out activation involved an integrin binding proteins inside the cell that convert it to high affinity.
- After ligand binding integrins can also cluster just like other cell adhesion molecules do, increasing the strength and stability of the cell-ECM adhesion.
Name the four functions of integrins.
- 1. Cell migrations - wound healing, neuron path finding, immune function
- 2. Cytoskeletal organization.
- 3. Signaling- regulate cell proliferation and regulate cell differentiation
- 4. Stable adhesion - muscle tendon attachment, attachment of different layers of the skin
Give an example of the clinical relevance of integrins.
Loss of beta4 integrin causes junctional epidermolysis bullosa.
Describe Focal Contacts.
- link to actin fibers
- common to many cell types
- can be composed of a variety of integrin heterodimers
- Very dynamic and used to generate traction forces on the ECM- therefore vital for cell migration
- Stable forms are important for muscle attachment to tendons
- link to intermediate filaments
- found exclusively in epithelial cells
- (alpha)6(beta)4 integrin heterodimer