Extracellular Matrix Flashcards
1
Q
what role does the ECM play in connective tissue?
A
carries mechanical load
2
Q
what role does the ECM play in epithelia?
A
holds epithelial tissues together, because the cells are directly jointed to each other via membrane junctions and carry mechanical loads themselves
3
Q
in epithelial tissue, where are components of ECM produced and secreted?
A
fibroblasts
4
Q
2 major types of ECM in the body?
A
- ECM associated with epithelial tissue (basal lamina)
2. ECM associated with connective tissue
5
Q
what are the major components of the basal lamina?
A
glycoproteins and proteoglycan
6
Q
major glycoproteins in the basal lamina?
A
laminin, type IV collagen, nidogen, fibronectin
7
Q
major proteoglycans in basal lamina?
A
perlecan
8
Q
unique fct of basal lamina in the kidney glomerulus?
A
lies between 2 cell sheets and functions as a selective filter
9
Q
what is basal lamina?
A
thin, tough, flexible sheet of ECM, essential component of epithelial cells, surrounds muscle cells, fat cells and schwann cells
10
Q
how is the basal lamina formed?
A
interactions between laminin, type IV collagen, nidogen and perlecan
11
Q
what do nidogen and perlecan do?
A
link laminin and type IV collagen networks
12
Q
where is laminin in the cell?
A
anchored at the cell surface through binding of their tail regions to receptors, but head regions are free to interact with other molecules, so it organizes the rest of the ECM sheet structure
13
Q
what is laminin in the cell?
A
major glycoprotein that is a heterotrimeric complex of alpha, beta and gamma subunits, primary organizer of the sheet structure because its ends can bind to multiple components of the basal lamina for structural support
14
Q
what does the long end of laminin bind to?
A
integrins, dystroglycans, perlecan
15
Q
what does the short end of the laminin bind to?
A
integrins
16
Q
what does the “armpit” of laminin bind to?
A
nidogen
17
Q
what 2 tissues is collagen an important component of?
A
connective tissue and basal lamina (epithelium)
18
Q
action of collagen
A
resists tensile forces
19
Q
buildup of collagen?
A
3 polypeptides (each called alpha chain)wound around one another to form superhelix, which then assemble into polymers called collagen fibrils, which then pack together to form collagen fibers
20
Q
which protein is the chief protein in bone, tendon and skin?
A
collagen
21
Q
what cells produce collagen ?
A
fibroblasts in the skin and tendons, osteoblasts in bone
22
Q
3 families of collagen?
A
fibrillar, sheet forming, anchoring/linking
23
Q
where are fibrillar collagens found?
A
bone
24
Q
where are sheet forming collagens found?
A
basal lamina
25
where are anchoring/linking collagens found?
skeletal muscle
26
what role does fibrillar collagen play in the eye?
provides optically clear path for light, because orthogonal collagen fiber layers make the transparent cornea, also forms the scaffolding for vitreous body
27
what role does fibrillar collagen play in bone?
type I collagen fibrils form layers reinforced by calcium phosphate crystals
28
what role does fibrillar collagen play in tendons, ligaments, bones, other dense connective tissue, and cartilage?
provides tensile strength, form scaffolding, resists compression, and attracts water via trapping glycosaminoglycans and proteoglycans
29
what post-translational modifications occur for collagen?
1. hydroxylation on prolines and lysines in the ER/Golgi compartment
2. glycosylation of hydroxylysines
3. cleavage by proteases
30
types of sheet forming collagens
type IV, type VIII and type X(?)
31
what is Descemet's membrane?
a special basement membrane under the endothelium of the cornea made of hexagonal nets of type VIII collagen
32
what sheet forming collagen is found in the basal lamina, around muscle cells and nerve cells?
type IV collagen, net like polymers
33
types of fibrillar collagen?
type I, II, III, V, XI
34
types of anchoring/linking collagens?
type VI, VII, XII and XIV
35
general function of anchoring collagens?
link fibrillar and sheet forming collagens to other structures
36
example of anchoring collagen in the basal lamina?
dimers of type VII collagen polymerize to form anchoring fibrils that link type IV collagen to basal lamina of stratified epithelia to plaques in the underlying connective tissue
37
what does type IX collagen do?
links glycosaminoglycans to type II collagen fibrils
38
action of fibroblasts?
main synthesizers of ECM components, synthesize collagen fibers as fibroblasts move through tissue, reorganize deposited collagen by crawling along them and pulling on them
39
what cell determines arrangement of collagen fibers in the ECM?
fibroblasts, that synthesize collagen as they move through tissues
40
pathology of osteogenesis imperfecta?
mutations in one or more collagen gene, resulting in poor quality of collagen or insufficient quantities of collagen, most prevalent = type I
41
what is osteogenesis imperfecta?
genetic disorder characterized by brittle bones, short stature and spinal curvature
42
pathology of type I-4 ehlers-danlos syndrome?
mutations in collagen genes, resulting in defective collagen synthesis
43
pathology of type 6 ehlers-danlos syndrome?
mutation in gene encoding lysyl hydroxylase, so collagen molecules are not hydroxylated and cannot be processed properly
44
function of lysyl hydroxylase?
adds hydroxyl groups to lysine
45
characteristics of ehlers-danlos syndrome?
hyper flexible joints, fragile skin, blood vessels easily rupture
46
what is fibronectin?
large glycoprotein composed of 2 subunits joined by disulfide bonds at one end in soluble form or insoluble
47
function of fibronectin?
provides cells a linkage to the collagen fibrils in the ECM through its interactions with integrins
48
2 forms of fibronectin?
1. soluble form in blood or body fluids
| 2. insoluble fibronectin fibrils in ECM
49
what are glycosaminoglycans?
highly negatively charged (hydrophilic) unbranched polysaccharide chains of repeating disaccharide units that are usually linked to core proteins (proteoglycans)
50
4 main groups of GAGs
1. hyaluronan
2. chondroitin sulfate/dermatan sulfate
3. heparan sulfate
4. keratan sulfate
51
GAGs in ECM
fill most of ECM due to their highly extended conformations that occupy a large volume relative to their mass, also because they are strongly hydrophilic they readily form gels at low concentrations
52
unique characteristic of hyaluronan (hyaluronic acid)
the only GAG not linked to a core protein, and therefore is not synthesized in the ER. therefore, not released from the cell via exocytosis, but spun out directly via hyaluronan synthase in the plasma membrane
53
complexity of hyaluronan?
simplest GAG of repeats of up to 25,000 disaccharide units
54
types of proteoglycans
aggrecan, decorin
55
what is aggrecan
a huge proteoglycan molecule that is a major component of cartilage
56
what is decorin
small proteoglycan that binds to collagen fibrils and regulates fibril assembly
57
how do aggrecans contribute to cell signaling?
1. binds to fibroblast growth factor (FGF), allowing them to cross link and activate their cell surface receptor
2. immobilizes chemokines at sites of inflammation
3. inhibits transforming growth factor beta (TGF beta) by binding and sequestering
58
what role do aggrecans play?
can combine with hyaluronan to produce very large aggrecan aggregates that are commonly found in the cartilage matrix to resist compressive forces
59
where is aggrecan made, processed and modified?
rough ER, addition of polysaccharide chain occurs in lumen of ER, additional modifications in golgi and is released via exocytosis
60
what molecules join together to make aggregates in the extracellular environment?
proteoglycan (aggrecan) and hyaluronan
61
synthesis of hyaluronan
made by hyaluronan synthase at the plasma membrane and is spun out directly
62
what is syndecan?
membrane spanning proteoglycan whose intracellular domain interacts with the actin cytoskeleton and signaling molecules within the cell
63
where is syndecan found?
on the surface of fibroblasts, they modulate integrin function by interacting with fibronectin on the cell surface (and via cytoskeletal and signal molecules inside the cell)
64
what is betaglycan?
proteoglycan found on cell surface that binds to TGFbeta and presents it to the TGFbeta receptors
65
action of aggrecans with TFGbeta?
inhibits it by binding and sequestering
66
what are elastic fibers?
loose and unstructured polypeptide chains that are covalently cross linked into a rubber like elastic meshwork
67
where are elastic fibers found?
ECM of connective tissue of smooth muscle, blood vessels, skin and lungs
68
action of elastic fibers?
allows tissues to stretch and then relax to their original form, usually collagen fibers are interwoven to limit extent of stretching and prevent tearing
69
2 components of elastic fibers?
elastin and microfibrils
70
what is microfibrils
polymers composed of glycoprotein fibrillin
71
function of neutrophil elastase
an enzyme that cleaves elastin that is produced by neutrophils in response to inflammation
72
result of alpha-1-antitrypsin deficiency
no alpha-1-antitrypsin to inhibit elastase, so elastin is destroyed, limiting elasticity of the tissue and giving rise to COPD or emphysema
73
what is alpha-1-antitrypsin
protease made in liver that inhibits neutrophil elastase
74
what is marfan syndrome?
disorder of connective tissue due to mutation in fibrillin-1 gene
75
pathology of marfan syndrome?
mutation in fibrillin-1 gene, leading to defects in elastin fibers. deficit in elastin fibers reduces sequestering of TGF-beta, so increased TGF-beta contributes to symptoms
76
characteristics of marfan syndrome
above average height, long, slender limbs, at high risk for aortal aneurysm and aortal dissection
77
how much of the aortal tissue is elastin fibers?
50%
78
function of elastin fibers with TGF-beta?
elastin fibers bind to TGF-beta and sequester it in the ECM, preventing it from binding to its receptor on target cells
79
what are matrix metalloproteinases (MMPs)
major class of tightly controlled enzymes that degrade ECM components, there are several members in the class that each have a specific target in the ECM
80
what do MMPs require to work
binding of Ca or Zinc
81
2 reasons why ECM degradation is important?
1. cell migration/room to divide
2. some growth factors are deposited in the ECM and must be freed by degradation of the ECM components to have access to their receptors on the surfaces of target cells
82
what are serine proteases on the MMP
have a highly reactive serine in the active site
83
how are MMPs regulated? (3)
1. local activation
2. confinement by cell surface receptors
3. secretion of protease inhibitors
84
example of a local activation degradation
plasminogen, an abundant inactive protease precursor in the blood, is cleaved by plasminogen activators near sites of blood clots to yield plasmin (to help break up blood clots)
85
what is plasmin
enzyme that helps break up blood clots, degrades fibrin
86
what is fibrin
ECM molecule that is a component of blood clots
87
example of confinement by cell surface receptor degradation
urokinase-type plasminogen activator (uPA), binds to receptors on growing tips of axons and the leading edge of migrating cells, degrades the ECM in front of them to clear a path for their migration
88
MOA of confinement by cell surface receptor?
cells have receptors on their surface that bind proteases, confining the enzyme to the sites where it is needed
89
which method do some cancer cells utilize for metastasizing?
confinement by cell surface receptors
90
example of secretion of inhibitors
tissue inhibitors of metalloproteinases (TIMPs), bind tightly to activated MMPs and block their activity. protect cell adhesion and migration proteins from being targeted by active MMPs
91
what may cancer cells express to help metastasize?
membrane type 1 matrix metalloproteinase (MT1-MMP), that activates other MMP-2 to further degrade ECM and break through the basal lamina
