Cell-substrate interactions 1 Flashcards
What is the extra cellular matrix
Collection of extracellular molecules that provides structural and biochemical support to the surrounding cells
It is DYNAMIC not static
What two parts form the ECM
Interstitial matrix
Basement membrane
Why is the ECM important
Needed for cell - migration, proliferation differentation, immune system and tissue repair
What makes up the ECM
Collagens
Elastins
Proteoglycans - hyaluronic acid
Glycoproteins - fibronectin and laminin
How many collagen genes are there and what do they code for
25 - alpha chains
What is the process of collagen assembly
Alpha-chain X3 –> Procollagen –> (CLEAVED) collagen fibril –> collagen fibre
Why is collagen important
Resist tensile forces
What is the role of type 1 collagen
Principle collagen of skin and bone and the commonest.
How does collagen form correctly to ensure it is the correct type
Requries integrins and other adhesion molecules.
How is the alpha chain triple-helix stabilised
Via hydroxyaltion of proline using vitamin C
How does scurvy affect collagen
Dont have vitamin C to stabilse these alpha helixes of the collagen
What are the features of type IV collagen
Flexible and assemble in sheet structure - make basal lamina
Why is collagen related to oestogenesis imperfecta
Type 1 collagen mutation that is autosomal dominant - weak bones and irregular connective tissue
Why is collagen related to ehlers-danlos syndrome
Weak and ruptured arteries caused by different types of mutations of collagen
Why is collagen related to alport syndrome
Mutations in collagen IV - mostly xlinked and have problems with sight, hearing and renal
Why is collagen related to knobloch syndrome
Autosomal recessive disorder which presents with myopia, cataracts, dislocated lens and retinal detachment
Why is collagen related to osteoporosis
Reduced density of collagen with age
What is the role of elastin
Gives elasticity to tissues
Why is eleastin interwoven with collagen
To limit stretching and prevent fibre tears
How is elastin formed
Tropoelastin and assembled into elastin fibres outside the cells in the plasma membrane. where they cross link and generate as sheets by lysine molecules.
What are proteoglycans
formed of glycosaminoglycans (GAGs) covalently attached to the core proteins.
What is the role of proteoglycans
Highly negative charge to attract positive cations to suck water into the matrix and provide a cushion
What are the 4 main types of proteoglycans
Hydroronic acis
Chondroitin sulfate
Heparan sulfate
Keratan sulfate
Differ depending on sugar
Where are proteoglycans important
Joints - hydronic acid
What is the role of glycoproteins
Mediate cell adhesion to matrix
What is the structure of laminin
3 chains - alpha, beta, gamma
How many genes if fibronectin is there
1 - alternative splicing makes different types of fibronectin
What type of fibronectin is soluble
Plasma fibronectin - all others are insoluble
Where is fibronectin mostly found
Surface of cells
How does fibronectin work
Integrins bind to RGD domain on fibronectin which stretches them
What are integrins
Large family of transmembrane proteins that function as the major receptors for cell adhesion via connecting intracellularly and extracellularly
How many integrins form
24 based off of 18 alpha subunits and 8 beta subunits - the combination decide the substrate affinity
RNA splicing gives different integrins
What are the main 4 collagen receptors
Collagen receptor
RGD receptor (fibronectin)
Laminin receptor
Leukocyte-specific receptor
Why do non-attached cells not grow
Require integrins for growth factor binding.
How are integrins activated
Talin binds intracellualrly which integrins undergo a conformational change to expose extracelluar binding part.
Go from bent to straight
Give an example of integrin binding
Platelet aggregation
How do integrins help cell migration
Looses affinity for site A and increases affinity for surface of site B which moves it towards B
Give two integrin inhibitors
ICAP
Sharpin
Give 3 integrin activatiors
Kindlins
Talin
KRIT1
Why does fibronectin not self-assemble
Self-assembling domains not exposed so need some force to stretch it to expose them
How does fibronectin assembly require
Actin - fibronectin binds to cell which causes intracellular signalling to form an actin cystoskeloton which stretches the cell and allows more fibronectin to binds
What is the ECM linked to inside the cell
Actin cytoskeleton via fibronectin
What causes muscular dystrophy
Defect in dystrophin which binds actin in muscle cells to fibronectin outside via integrins.
Give the three areas of cell adhesion issues
Defects in matrix/assembly - scurvy, ehlers-danlos syndrome
Defects in ECM receptors - leukocyte adhesion deficency
Defects in cytoskeleton proteins - muscular dystrophy
How can staph aureus cause cell adhesion issues
Has evolved a way to enter cells - binds to fibronectin which the fibronectin binds to integrin allowing the staph aureus to attach to the cells and change the cell shape to allow it to be englufed by the cell but stay alive, making it more resistant to antibiotics and stay hidden.
What role does hyaluronic acid have in cancer
WIDER READING - Stern 2005
Higher levels of hyaluronic acid on cancer cells are indicators of a worse outcome.
Its receptor CD44, participates in cell adhesion interactions which are required by tumour cells.
How has hyaluronic acid been used in cosmetics
WIDER READING - Gold 2007
As it can attract water, it is used as a dermal filler to hide wrinkles.
Where is hyaluronic acid important in cell adhesion
WIDER READING - Litwiniuk, M; Krejner, A; Speyrer, MS; Gauto, AR; Grzela, T (2016)
Formation of granulation tissue as it produces a hydrated matrix to allow cell migration.
It forms links with protein kinases associated with cell movemement (extracellular signal-regulated kinase etc)
Why is collagen so useful in bone grafts
WIDER READING - Cunniffee 2011
Cannot be broken down by enzymes due to its triple-helix structure, allowing cells to attach and form an effective ECM.
What roles does collagen have in wound healing
WIDER READING - Rangaraj 2011
Guides fibroblasts to migrate in ECM
Haemostatic - cell adhesion of platelets to form haemostatic plug.
Benefits as a wound dressing due to antibacterial properties
What is the pathogenesis of osteogenesis imperfecta
WIDER READING - Xiao 2011
Glycine substitute to alanine which is bigger, causes buldges in collagens triple helix structure which influenceses its interaction and binding and impairs them.
Multitude of other pathphysiologies but this is one of them
How does osteogenesis imperfecta present
WIDER READING - LEE 2019
Hearing loss, breathing problems, blue sclerae, loose joints, dental issues, short stature
What is the pathophysiology of alport syndrome
WIDER READING - Nozu 2019
Mutations in 3/6 collagen genes - COLD4A3, COL4A5, COL4A4
Important for the basement membrane in the kidney, inner ear and eye causing issues in these
Give some ligands for integrins
Fibronectin
Vitronectin
Collagen
Laminin
How do integrins help cells move
WIDER READING - Paul 2015
The ones at the front bind to the ECM whilst the ones at the back are endocytosed and moved to the front of the cell via the endocytic cycle where they are added to the front surface.
What is the role of integrins in nerve repair
wider reading - Nieuwenhuis 2018
Present at the growth cone in damaged PNS neurons and promote axon regeneration
How does laminin help in neural development
WIDER READING - Sarthy 1990
Lays down path for growth cones to follow of the retinal ganglion cells to get from the retina to the tectum.
Is fibronectin important
WIDER READING - E L George 1993
Needed for embryogenesis as results in neural tube and vascular development defects when inactivate the fibronectin gene in mice.
(Mesodermal defects)
What transmembrane protein is essential for fibronectin matrix formation
WIDER READING - Lugano 2018
CD93 - if knockedown then these cells result in a distruption of fibrillogenesis in both human blood endothelial cells and the retina
Explain the pathophysiology of Ducheene’s muscular dystrophy and how that relates to
WIDER READING - Niggli 2008
Genetic mutation in dystrophin gene which is responsible for connecting actin cytoskeleton to the basal lamina within muscle fibres.
When dystrophin is absent, calcium accumulates which lies within the cell membrane which causes water to move into the cell due to signalling pathway changes and causes mitochondria to burst causing muscle cell death
