Extracellular Matrix Valenick Flashcards
The communication b/n a cell and the ECM is mediated by what type of cell surface receptor?
Intergrins
when connections get disabled b/n the ECM and the cell, what can result?
congenital diseases such as DMD, Marfan syndrome etc.. Cancer and suseptibility to Infectious diseases
what type of receptor has bidirectional signaling, helps to modulate the ECM deposition & gene/protein expression and directly links the ECM to the intracellular cytoskeleton?
Integrins
integrins act as (blank), meaning they are activated by physical stress and stimulate a chemical response from the stress.
mechanotransducers
Integrins can stimulate 6 different pathways, what are they?
1) regulate gene expression
2) alter cytoskeleton organization
3) recruit additional integrins to cell membrane
4) promote cell growth
5) influence cell survival
6) promote ECM deposition
what is another term for promoting cell growth?
hypertrophy
what is mainly composed of proteins and carbohydrates, and forms and maintains the tissue architecture?
Extracellular Matrix (ECM)
what are two sub-types of ECMs?
interstitial (stromal) ECM & basal lamina ECM
Interstitial ECM is located where?
it surrounds cells and tissues and is abundant in connective tissue and it contains fibronectins
where is Basal lamina ECM found?
ECM is seen as the electron dense layer of the basal lamina (a component of the basement membrane).
what are the major components of the ECM?
Collagen, fibronectin, laminin, elastin, glycosaminoglycans, & proteoglycans.
what is the most abundant component of the ECM?
collagen- rope-like fibers that give tissue tensile strength.
what ECM component is mainly located in teh bones, tendons, skin, cartilage, arteries, lungs and liver?
Collagen
Collagen 1 and 2 form what type of triple helices?
left handed alpha-helix of 1000 AAs with a repetitive sequence of (Gly-X-Y)n
30% is glycine, 25% proline/hyroxyproline at X & Y
the assembly of 3 alpha chains into a right handed super helix is called what?
tropocollagen
how is procollagen formed?
Preprocollagen is synthesized in the ER where it forms a polyproline helix, the signal sequence is removed leaving procollagen
how is tropocollagen generated?
1) disulfide linkages occur between the alpha chains
2) various prolines and lysines are hyrdoxylated
3) collagen is O-glycosylated on hydroxylated lysines and N-glycosylated on asparagines
4) 3 alpha chains assemble into Rt handed helix
5) secreted from cell and ends are cleaved
what is responsible for the hyrdroxylation of lysines and prolines of collagen? and what do they require?
lysyl and prolyl hydroxylases that require Vitamin C
what type of integrin complex is affected in Muscular dystrophy?
dystoglycan complex integrins
Integrin receptors have very diverse specificity, including receptors for (blank)
collagen receptors, laminin receptors, leukocyte specific receptors, platelet receptors and RGD receptors.
in addition to the cytoskeleton, integrins can also link (blank).
the nucleus (lamin A)
what is a structural-functional component of striated muscle cells which connects the sarcomere of the muscle to the cell membrane.
Costamere
Independent of genotype, the ECM stiffness guides stem cell differentiation. What grew on the 3 ECM platforms (soft, firm, hard)
soft- nerve
firm- muscle
rigid- bone
what is the pathway that links the micro-environment to the chromosomes?
ECM-Integrin-Cytoskeleton-Nucleus-DNA
what is responsible for the covalent cross-linking found in tropocollagen?
lysyl oxidase- oxidative deamination of lysine and/or hydroxylysine - Cu2+ is required.
cross-links are major determinant of what?
mechanical properties and strength of tissues
what is a glycosylated multi-adhesive protein found in connective tissues and plasma?
Fibronectin
there are two types of Fibronectin, what are they?
soluble form found in plasma
insoluble form found in the ECM
both encoded by 1 gene with alternative splicing
what does Fibronectin interact with?
interacts with integrins via its RGD sequence and many other ECM components
what are the roles of Fibronectin (Fn)?
1) development- essential for migration of cells along fibers
2) wound healing-links to fibrin clots to promote healing
3) cancer- cancer cells have Fn receptors that can bind ECM Fn at distant sites faciliating metastasis
4) cell proliferation and migration
what is laminin (Ln)?
a multi-adhesive component enriched at the basal lamina where it binds cells to collagen 4
cross-shapes heterotrimer
has multiple isoforms
associated with cell differntiation
what is laminin 2?
basement membrane protein that links integrin (or dystroglycan) to other ECM components
what is lamin A
a nuclear envelope protein that forms filaments
what is lamina?
the ECM component of basement membrane seen by electron microscopy
what allows tissues to expand and contract?
Elastin
where is Elastin most abundant?
blood vessels and lungs
what has a highly cross-linked structure that is insoluble and rich in lysine, proline, valine, and glycine?
Elastin
what does elastin use to initiate cross-linking?
lysyl oxidase
what is the cross-link formed in elastin called?
desmosines
dermatan, chondroitin, heparan, & heparin are the most common (blank).
glycosaminoglycans
what are glycosaminoglycans (GAGs)?
unbranched polysaccharides of repeating disaccharide units built from amino sugars and uronic acids.
what is the only true GAG?
hyaluronic acid
Most GAGs are complexed to core proteins forming (blank).
proteoglycans
what are the roles of GAGs and PGs?
provide flexible mechanical support?
act as sieves allowing the diffusion of small molecules and slowing the movement of proteins and movement of cells.
acts as a lubricant in joint and tissues subject to friction.
binds and sequestered soluble ECM proteins, thereby maintaining high concentration at the cell surface.
what do Matrix Metalloproteinases do?
breakdown the ECM allowing the release of sequestered growth factors and allow for migration and tissue remodeling during development and response to injury.
ECMs function in Cancer
ECM signals maintains dormant tumor cells, when the ECM is disrupted and reconstructed fibronectin and growth factors promote micrometastatic outgrowth.
scurvy
abnormal collagen
Marfan Syndrome
mutation in Fibrilin
Mucopolysaccharidoses
mutation in proteoglycans
Osterogenesis Imperfecta
mutation in collagen
Supravalvular aortic stenosis
Elastin insufficiency
