Extracellular Matrix and Cell Adhesion Flashcards
What are the functions of the ECM
- Functions as an adhesive substrate
- Structure
- Presents growth factors to their receptors
- Sequesters and stores growth factors
- Senses and transduces mechanical signal
what does the ECM regulate
- Proliferation
- Differentiation
- Migration
- Cell to cell interactions
What cells make the extracellular matrix
- Collagens
- Elastin
- Glycoproteins
- Proteoglycans
What does the macromolecule network form
forms a 3D gelatinous (jelly like) bed for cells to live in
changes in the ECM underlie…
many chronic diseases
What is a precursor
- It is a substance from which another usually more active or mature substance is formed
e. g. tropocollagen polymerises into collagen
what protein mass make in the body
- 25% of total protein mass in the body
what is collagen made up of
- 34 related but distinct peptide chains
How many different types of collagen are there
- 19 different types
what are the two main families of collagen
- Fibril forming
- Non fibrillar – mesh like
what is the classic structure of collagen
- Triplet helix formed by 3 peptide chains
- Every 3rd amino acid is glycine
- Glyc – X – Y (proline or hydroxyproline)
- X is random hydroxyprolien
what types are fibril forming collagen
- type I and type II
- type I is strong and in bones
- type II is cartilage and is not as strong
what are the types of non fibril forming
- network forming
- FACITs
- transmembrane
- multiplexin
what type collagen is network forming
type IV and type VI – separates different cell types from each other
what type of collagen is FACITs
– type IX XII, XIV – act as cell attachment, glycoprotein addition that helps hold the triple helix into the membrane of the cell or onto the extracellular matrix
what type of collagen is transmembrane
type XIII, XCII, XXIII, XXV
what type of collagen is multiplexin
– type XVIII
describe mutation of osteogenesis imperfect
- Missense, non-conservative mutation
- Glycine is needed for a tight triple helix formation
- Even changing one amino acid from glycine to another bulkier amino acid will loosen the helix, changes from glycine to alanine or serine and others have been found
what is osteogenesis imperfect
- brittle bone disease
what is the defect in collagen in osteogenesis imperfecta
- Fragile bones
- Thin skin
- Abnormal teeth
- Weak tendons
- blue sclera (white of eyes are thin so they look blue)
Single base change - Converts glycine to a more bulky amino acid thus deforming the triple helix structure as glycine is the smallest amino acid which helps the collagen pack tightly into a triple helix
what are the two different types of osteogenesis imperfect
- type I is autosomal dominant
- type II is more sever
describe type I osteogenesis imperfecta
- Type I is autosomal dominant
- 50% of of cases
- Mildest
- Mutation on Chromosome 17 COL1A1 gene
- Mutation on Chromosome 7, COL1A2 gene
describe type II osteogenesis imperfecta
- Usually new mutation (de novo) – don’t see as they don’t survive
- Bone break during birth process therefore babies don’t survive
- But it would be dominant if affected individuals survived
describe elastin
- Flexibility required for blood vessels, lungs, ligaments and skin
- Stretch in 2 dimensions
- There is an outer supporting coating of fibrillin that gives it more structure and tame it with fibrillin
- Rich in glycine and proline like collagen
- Have more valine that interacts with hydrophobic domains giving it elasticity
- More elastin fibres give more flexibility than collagen
what is Marfan syndrome caused by
- Elastin fibres are normal by fibrillin protein are mutated
- Elastin fibres covered by glycoprotein fibrillin which gives the fibres stability
- If fibrillin misfolded this changes ECM properties
what are the symptoms of Marfan syndrome
- Creates tall stature
- Long arms and legs
- Spider fingers – arachnodactyly
- Loose joints – joints can dislocate
- Floppy cardiac valves
- Eye problems – lens is suspended by a ligament, and lens can dislocate
- Aortic aneurysms
what happens to the fibrillrin protein in marfans
- In marfans patients TGF- BETA is not bound with ECM – it accumulates in lungs, heart and other tissues which changes ECM in these organs especially where there are lots of elastic fibres
- autosomal dominant disease
- mutant misfiles the firbillin therefore making the elastic fibres too stretchy
what are the glycoproteins
- carbohydrate and protein
- fibronectin
- laminin
what glycoproteins form what receptors on the cell surface on what cells
- Bacteria
- Viruses
- Toxins
- Hormones
- Other cells
describe the function of carbohydrate and protein glycoproteins
Act as receptors on cell surface
Provide strength and support for ECM
Form the slime layer of bacteria
what its the function of fibronectin
- cell adhesion
- cell migration
- cell shape
- cell differentiation
- cytoskeleton organisation
what is the function of laminin
- Cell adhesion (basement membrane)
- Cell migration
- Cytoskeleton organisation
describe the structure of proteoglycans
- Gel forming components of the ECM
- Peptide chains with covalently bound sugars – proteins conjugated to polysaccharides with serial repeat units
- 95% carbohydrate - GAGs (glycosaminoglycans) and mucopolysaccharides
- Multiple side chains of GAGs
- Sulphated – gives them an extra negative charge
describe proteoglycan aggregates
- In most tissues’ proteoglycans form large aggregates
- Form a jelly like matrix
- Draws and holds water in the tissue because of the negative charge of GAG chains
- Give compressive strength to tissues
describe age and proteoglycans
- Long in new-borns, get smaller with age, less side chains and smaller protein cores
- Connective tissue gets drier cannot attach as much water therefore more brittle and cannot resist compressive forces, dissolved nutrients can get through
what are the 5 major protein families in cell adhesion
- Cadherins
- Ig super family
- Selectins
- Mucins
- Integrins
what are the different types of adhesions
- Homophillic (homotypic) adhesions connect between the same molecules
- Heterphillic (heteroptypic) adhesion between different types of molecules (selectins and mucins)
How does cell migration work
- actin filaments polyermise to change the shape of the cell
- adhesion proteins form new adhesions on the surface, they are linked to the actin filaments which now contract to make the cell more forwards
- adhesion proteins at the back end death from the surface to allow the cell to move forward
- Forces produced by contractile network combined with actin filament and disassembly help to retract the trailing cell edge
what does cell migration on a flat substrate lead to
- it can lead to detachment and apoptosis
- in reality it need the ECM for cells to be able to migrate
describe an example of cell migration
leukocyte extraversion contains the steps - chemoattraction - rolling adhesion - tight adhesion - endothelial transmigration
what happens when cell adhesion and migration go wrong
cancer
Describe how cancer metastasis works
- In tumour cells, epithelial to mesenchymal transition (EMT) – inducing transcription factors
- Loss of cell adhesion and loss of apoptosis
- Basement membrane breaks down allowing cells through into the blood stream
- Then find a new location to start the cancer again
what are macromolecules secreted as
they are secreted as smaller precursors such as tropocollagen but once they are outside the cells they polymerise so for example tropocollagen polymerises into collagen
where is type I collagen found
skin, tendon, bone, most loose/dense CT
where is type II collagen found
hyaline cartilage (fibrocartilage has both 1 and 2)
where is type III collagen found
liver, lymphoid organs (spleen, bone marrow, lymph nodes)
Reticular fibres
Loose CT may contain some type 3, along with type 1
where is type IV collagen found
basement membrane
what does fibrillin do on the ends of the elastic fibres
Gives stability
Helps anchor fibre to other ECM proteins
Modulates amount of TGF-β (a growth factor)
explain how cell migration and cancer works
Cancer alters the ECM
- Make enzymes to cleave cell-adhesion molecules &break down ECM proteins
cells become loose helps migration metastasis
- Growth factors and cytokines facilitate migration and metastasis
