anat8.txt

The ECM is a substance secreted by cells into their outside environment.  It is composed mainly of proteins and complex polysaccharides.  

• 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)

Connective tissue and basement membrane

• 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

• resists compression
• permits diffusion of nutrients and wastes between cells

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

• glycosaminoglycans (GAGs)
• proteoglycans (PGs)
• glycoproteins (GPs)

a chain of carbohydrates

The process of adding carbohydrates to proteins.

• glycosaminoglycans
• 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

Failure to break down GAGs causes mucopolysaccharidoses (MPS) diseases ie. dwarfism, mental retardation, cardiomyopathy, etc

• GAG
• the only GAG that does not bing proteins directly
• good lubricant - found in joints
• many biological and medical roles - wound repair, cell migration, inflammation

• 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).

• PG: Aggracan - major component of cartilage
• GP: Fibronectin - key molecule in blood clotting and tissue repair

• fibroblasts 
• adipocytes
• chondroblasts
• osteoblasts
• tendon cells

Fibroblasts

The interface between epithelium and connective tissue (under light microscopy).

• 1.  Basal lamina - produced by epithelial cells
• 2.  Reticular lamina (aka lamina reticularis) - produced by the connective tissue

• mechanical barrier
• anchor (firm and flexible support) for the epithelium
• molecular filter for the epithelium

• 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.

• collagens I and III
• anchoring fibrils (type VII collagen fibers)
• GP Fibrillin

• Epithelial cell
• laminin
• lamina lucida
• lamina densa
• basal lamina
• reticular fibers (type III collagen)
• anchoring plaque (type IV collagen)
• anchoring fibrils (type VII collagen)
• lamina reticularis

Mutations in collagen IV (component of anchoring plaques) cause Alport syndrome; may result in kidney failure, hearing loss, cataracts

• 1.  Hemidesmosomes (anchoring junctions)
• 2.  Focal Contacts (anchoring junctions)

• 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.

• 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

• 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.

• 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

Loss of beta4 integrin causes junctional epidermolysis bullosa.

• 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