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In connective tissue, the main stress-bearing component is the ___.
ECM
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In epithelial tissue, the ___ form the main stress-bearing component.
cytoskeletons of the cells themselves (linked by anchoring junctions)
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What is the purpose of the ECM?
- Provides scaffolding and support for tissues and cells.
- Signal transduction.
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What makes up the ECM?
proteoglycans, collagen, laminim, fibronectin, and vitronectin.
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Describe proteoglycans?
"filler" substance. Traps water. Binds cations.
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Describe collagen?
Most abundant ECM component. Connective tissue.
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Describe laminin?
Forms network of weblike structures that resist tensile forces.
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Describe fibronectin?
Glycoproteins. Maintains cell shape.
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Describe vitronectin.
Glycoprotein. Promotes cell adhesion and spreading.
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What are two principles of tissue formation?
- Cells must be attached to each other.
- Cells must be attached to a scaffold.
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Why must cells be attached to each other?
Protein-protein interaction between cells.
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Why are cells attached to a scaffold?
- Cells secrete proteins and carbs which make up the ECM.
- Intermembrane proteins connect the ECM with the cell's cytoskeleton.
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What types of proteins are used in cell adhesion?
Cadherins, selectins, integrins, Ig family
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Describe cadherins.
Tissue specific; dimerize; Ca+2 dependent; regulate cell shape and migration.
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Cancer cells also change ___ expression.
cadherin
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Cadherins affect cell shape and migration via ___.
Indirect binding
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Describe selectins.
- Cell adhesion molecules that bind to sugars.
- Type of lectin.
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In wound-clotting, what is selectin-dependent?
Weak adhesion and rolling.
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In wound-clotting, what is integrin-dependent?
- strong adhesion and emigration
- Lets white blood cells exit capillary
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What are three kinds of cell junctions?
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Describe adhesive junctions.
- Desmosomes and adherens.
- Hold cells together in fixed positions w/in tissues.
- Ca+2 dependent.
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What are two types of adhesive junctions?
Desmosomes and adherens (both Ca+2 dependent)
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Describe the structure of desmosomes.
- Keratin intermediate filaments connected to plaque.
- Plaque composed of anchor proteins.
- Transmembrane cadherin adhesion proteins attached to plaque.
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What makes up the transmembrane cadherin adhesion proteins?
desmoglein and desmocollin.
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What proteins make up the plaque?
- desmoplakin
- plakoglobin
- plakophilin
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What is the purpose of the intermediate filaments attached to the plaque?
structural support (not movement)
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Describe tight junctions.
- Seal space between cells.
- Prevent flow of molecules and ions thru EC space.
- Important for organs that store liquids.
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What proteins make up tight junctions?
claudin and occluding
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Describe gap junctions.
- Most common type of junction between animal cells.
- Form open channels between cells allowing ions and small molecules to pass.
- Useful for cell-cell communication.
- Open at low Ca+2 and low pH
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What binds to gap junction to open the channel?
calmodulin (also binds to calcium)
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What kind of molecule can pass thru a gap junction?
small (e.g. cAMP)
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How is the ECM formed?
Secreted by the cells
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Describe integrins.
- Used in cell-cell adhesion.
- Serve as attachment to ECM.
- Bind to specific ECM proteins.
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Describe how collagen fibers are formed.
- Procollagen triple-helix formed in ER/Golgi complex.
- Single procollagen molecule out via secretory vessicle.
- Cleavage of propeptides.
- Thousands of collagen molecules form fibril in ECM.
- Aggregation of fibrils form collagen fiber.
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What is the purpose of proteoglycans?
- Trap water and provide elasticity (e.g. skin).
- "Filler" substance.
- Hold ECM in place.
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Describe structure of proteoglycans.
- 95% carbs by weight.
- glycosaminoglycan (GAG) is main component.
- Single polypeptide with hundreds of GAGs.
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What holds the ECM in place?
Linkages of proteoglycans to cell membranes.
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What are three types of interactions for proteoglycans?
- Receptors.
- Binding to ECM.
- Integrins binding to proteins in ECM.
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What are two adhesive glycoproteins?
fibronectin and laminin
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What's the main purpose of Fibronectin?
Provides/maintains cell shape.
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Describe fibronectin structure.
- Two large polypeptides (not identical) linked by disulfide bridges.
- Some domains bind to ECM.
- Other domains bind to membrane receptors.
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How is fibronectin specificity determined?
By the a.a.'s flanking the RGD motif
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What are integrins?
- Receptors that mediate attachment between cells and ECM/other cells.
- Critical for growth, hemostasis, and host defense.
- Interact with cytoskelton.
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Describe integrin structure.
- Heterodimeric with alpha and beta subunits.
- Variable subunits - mammals have 18 alpha, 8 beta
- e.g. melanoma: alpha-v, beta-3
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Describe the integrin receptor.
- Binds to soluble and attached ligands.
- Binding changes conformation of the dimer.
- Binding is Mn+2 dependent.
- Clustering occurs with other integrin receptors upon ligand binding.
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What are the two types of integrin activation?
- Outside-in - info from outside to cell
- Inside-out - info from cell to outside
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Integrins can bind to the ___, with a ___ of integrins.
same target, cluster
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What is anoikis?
Cells cease to be bound to ECM leading to cell death
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What are the typical results of integrin signalling?
Cell death, cell migration, cell shape change, cell division
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What does integrin clustering do in normal cells?
Affects cell migration and differentiation.
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What does integrin clustering do in cancer cells?
Angiogenesis and metastasis
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How does integrin clustering affect FAK and MAPK pathways?
- Focal adhestion tyrosine kinase -> cell survival
- MAP Kinase -> differentiation, cell growth, apoptosis
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