Adhesion of Cells and the Extracellular Matrix Flashcards
What are the components of connective tissue?
- Cells (scattered)
- Extracellular matrix
- Fibrillar proteins
- Hydrated gel of GAGs
- The majority of GAGs are linked to specific proteins to make proteoglycans.
Which cells are found in connective tissue?
- Fibroblasts
- Myofibroblasts
- Blood derived cells
- Mast cells
- Plasma cells
- Macrophages
- Chondroblasts - cartilage
- Osteoblasts - bone
- Adipocytes
What are the components of the connective tissue extracellular matrix?
- Fibrillar proteins
- Collagen - strength
- Elastin - stretch
- Fibronectin - enables networking
- Laminin - enables networking
- Polysaccharides glycosaminoglycans (GAGs) (in proteoglycans)
Describe the structure and function of fibroblasts.
- Large cell (because it carries out protein synthesis).
- Long extensions.
- Synthesises and secretes collagen, elastin and proteoglycans.
Decribe the production of collagen.
- Starts with a procollagen molecule in the RER.
- Hydroxylation of proline and lysine residues in the RER.
- Then, glycosylation of the molecule which adds either galactose or glucose to some lysine residues.
- Once this happens, the molecule becomes a triple helix.
- Then, this procollagen is secreted into the golgi, then into the EC matrix.
- Once procollagen is in the ECM, enzymes called procollagen peptidases cleave the terminal ends of the procollagen.
- Once it has cleaved the ends at the N and C terminal, the molecule is tropocollagen (highly insoluble).
- Tropocollagen molecules can aggregate to form collagen fibrils.
- Tropocollagen molecules become reinforced by hydroxy-lysine cross-links between molecules when 2 are in close contact.
- These cross links are formed by the lysyl oxidase enzyme.
Describe the structure of a collagen fibril.
Many staggered collagen molecules that are linked by the lysine hydroxylysine cross links which are formed by the lysyl oxidase enzyme.
How is collagen packaged in the RER?
Collagen is packaged into specialised (large) vesicles.
Where and how does collagen secretion occur?
Collagen secretion occurs by exocytosis at specialised sites.
Where are collagen fibrils produced and how are they organised?
- In a membrane tube called a fibripositor.
- Cells organise the collagen fibrils they secrete into fibres.
Describe the components of elastin.
- Fibrous protein secreted by fibroblasts and other cells.
- Elastin likes to exclude water.
- Hydrophobic effect is the main driving force for recoil.
- Made in fibroblasts and also smooth muscle cells and chondroblasts.
What are proteoglycans?
Assemblages of glycosaminoglycans and proteins.
What is the function of proteoglycans?
- Provide:
- Matrix support / cushioning / hydration
- Glue-like function
- Links between protein of the ECM and cell surface
Describe GAGs
- Long chains of repeating disaccharide units
- Highly charged (negative) and highly hydrated
Describe how the extracellular matrix is linked to the intracellular cytoskeleton.
- Collagen / proteoglycans bind fibronectin that links to integrins which themselves bind via adaptors to the actin cytoskeleton.
- Fibronectin acts as an adaptor protein on the outside.
- Integrins bridge the membrane.
Describe the structure and function of a myofibroblast.
-
Bi-functional
-
Fibroblast-like
- Secrete collagen
- Smooth muscle-like
- Synthesise actin, myosin and desmin
-
Fibroblast-like
Describe the involvement of myofibroblasts following tissue damage.
- Proliferate.
- Secrete collagen (scaffold).
- Consolidate damaged area (fibrous scar).
- Contract (reduce size of damaged area; express focal adhesions and smooth muscle actin).
How are myofibroblasts formed and why are they important?
They differentiate from fibroblasts under mechanical tension - especially important in wound healing. Also active in tissue fibrosis eg. liver cirrhosis.
Which type of cell is shown?
Mast cell (granules contain heparin and histamine).
Which type of cell is shown?
Plasma cell (antibody production is through the secretory pathway).
Which type of cell is shown?
Macrophage (ingesting listeria bacteria / paramecium).
What are the functions of adipocytes?
- Insulation (subcutaneous)
- Packing (eg. the eye)
- Energy storage
Describe the structure of an adipocyte.
- Peripheral cytoplasm
- Nucleus in the periphery
What is leptin responsible for?
The satiety signal
What is the function of cell junctions?
- Cell junctions / adhesion proteins link cells an their cytoskeleton to:
- Other cells
- And to the extracellular matrix
What are the 4 types of cell junction?
- Tight junction
- Adhesion belt
- Desmosome
- Gap junction
What are the different types of cell-cell adhesion?
- Integrin
- Selectin
- CAM
- Focal adhesion
- Hemi-desmosome
- Membrane proteoglycan
What are the functions of tight junctions?
- Define polarity (fence-off membrane lipids and proteins).
- Control the passage of substances between cells.
- Can link to actin cytoskeleton.
Describe adherens junctions.
- Plaque anchors actin filaments at the membrane (not intermediate filaments).
- Not as dense as desmosomes.
Distinct cadherins provide cell adhesion in different tissues.
Give examples of this.
- E-cadherin - epithelia
- N-cadherin - neurons and heart muscle
- P-cadherins - placenta and epidermis
- VE-cadherin - endothelial cells
Decribe desmosomes.
- Link between strong intermediate filaments in adjacent cells.
- Desmosomes are for strength.
- Found in the skin.
Describe the plaque and the filaments of desmosomes.
-
Plaque
- Cytoplasmic dense plaque containing desmoplakin and plakoglobin proteins.
-
Filaments
- Keratin filaments (tonofilaments) anchored to the cytoplasmic dense plaque.
Describe gap juctions.
- For communication
- Hydrophilic channel
- Small molecules pass
- Coordination of function (important in the heart muscle).
Describe focal adhesions.
- Focal adhesions link the outside of the cell (ECM) through transmembrane proteins (integrins) with the cytoskeleton (actin filaments).
- Dynamic (eg. in fibroblasts).
- Also act as signalling platforms.
- Link to fibronectin.
Describe hemidesmosomes.
- Hemidesmosomes link the outside of the cell (ECM) through transmembrane proteins (inegrins) with cytoskeleton (intermediate filaments).
- More stable (eg. linking epithelial cells to the basement membrane).
- Link laminin in the basement membrane.
What are integrins?
A large family of proteins which bridges between cytosol and the ECM.
Describe the molecular defect in Duchenne Muscular Dystrophy and how this leads to muscle dysfunction.
- Gene mutation - absence of dystrophin (adaptor) due to premature termination of translocation.
- Causes:
- Damage to mucle fibres due to muscle tearing
- Muscle wasting
- Muscle weakness
- Unable to walk by 12 years
Outline the recent experimental approach to correct the defect associated with DMD.
- PTC 124 (ataluren) is an experimental drug.
- It is thought to override the premature stop signal mutation to produce normal dystrophin.
- It also sems to work in the defective cystic fibrosis gene.
- Findings:
- Increasing doses of ataluren includes increased retention of dystrophin.
- NICE approves ataluren for treatment of DMD.
Describe the role of cell adhesion in cancer progression.
- Tumour cells accumulate (mutations disregulated cell cycle).
- Cells have not breached the basement membrane.
- Carcinoma is in situ.
- Cells undergo epithelial to mesenchymal transition (EMT).
Describe microinvasion of cell adhesion molecules in cancer.
- Cells convert to ‘mesenchymal’ cells and expression of cadherins is reduced.
- Microinvasion starts aided by actin-based protrusions called invadopodia.
- Secretion of metalloproteases (MMPs).
- Basement membrane breached.
- In invading tumours leading cells express inegrins promoting interaction with ECM and non-epithelial cells during movement.
Describe the role of cell adhesion in cancer when progression of metastasis occurs.
- Autocrine motility factors from tumour (increases motility of tumour cells and decreases E-cadherin).
- Angiogenesis factors (promote vascularisation).
- Entry into and through lymphatics and blood vessels.
- Dissemination - metastasis.
