55-140 Lecture Notes - Collagen, Amino Sugar, Cell Adhesion

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CELL ADHESION AND THE ECM
Principles of cell adhesion:
1. individual receptors have low affinity; many receptors have high AVIDITY
2. ADAPTER protein bridges necessary between cytoskeleton and receptor
3. Mix of adhesion receptors determines precise interaction
4. Adhesiveness is highly regulated
5. Signaling roles
6. Specific ligand binding activity and biological function
ANCHORING JUNCTIONS
Actin Filaments Intermediate Filaments
CADHERIN receptor ADHERINS DESMOSOME
INTEGRIN receptor FOCAL ADHESION HEMIDESMOSOME
(ECM) (Basal Lamina)
Receptors:
Cadherins – homophilic
junctional
IgCAM – homophilic or heterophilic
transient
Selectins – heterophilic (blood and endothelial)
sugar residues are ligand
transient
Integrins - heterophilic (only one that can bind ECM)
junctional
LEUKOCYTE EXTRAVASATION
1. infected endothelial cells present P/E SELECTINS
2. Leukocytes form transient adhesions with selectins
3. Leukocyte B2 INTEGRIN is activated
4. Integrins bind endothelial ICAM firm adhesion
5. Leukocytes squeeze through layer into damaged tissue
ADHESION MODULATION –
1. Selection expression of cell adhesion receptors
transcriptional
post-translational (stored in granules)
2. state of activation of receptor changes by CONFORMATIONAL change
3. Aggregation (at leading edge of moving cell for example)
INTEGRIN BIDIRECTIONAL SIGNAL TRANSDUCTION –
Inside-Out: activating signal (extracellular) activates INTRAcellular cascade
integrin is activated in the end and binds appropriate ligand
Outside-In: integrin binds extracellular ligand
cytoplasmic tail conf. changes
activates protein kinases
ex/ FAK autophosphorylates when integrins bind ECM ligands
FAK activates GRB2 (MAPK pathway)
“anchorage dependence” – cell cycle activated by GF’s AND integrin ECM binding
dependence is lost in cancerous cells
Integrins bind RGD (Arg-Gly-Asp) sequences in ECM proteins
each integrin has a specific ligand and biological function
ECM MACROMOLECULES – 5 classes to produce a great variety of ECM
1. ADHESIVE GLYCOPROTEINS – mediators between cells and ECM (adaptors)
domains: ECM binding sites
surface receptor (integrin) binding sites
FIBRONECTIN (FN) –
homodimer connected at C term (tweezer shaped)
RGD motif for integrin binding
also binds collagen, heparin
assemble into fibrils (insoluble) or in plasma (soluble)
each domain is a linear array of modular repeats beads on string
20 types from a single gene (alt. splicing)
**adhesion, cell growth regulation**
2. COLLAGEN – very strong polymers
trimer (triple helix)
strength from ability to tightly pack (conferred by GLYCINE)
more than 20 types (different combinations of alpha monomers)
subclasses (4)
1. FIBRILLAR – bone, cartilage, other CT
2. SHEET FORMING – basal lamina; 2D network
3. FIBRIL-ASSOCIATED – link collagen fibrils to one another, or ECM
4. ANCHORING FILAMENTS – anchors epidermis BM to dermis ECM
Biosynthesis:
1. pro-alpha chains synthesized in ER
2. ER: hydroxylation, glycosylation of prolines and lysines
3. ER: C termini are linked to initiate triple helix formation
4. procollagen forms (3 helices “zipper” together);
propeptide domains (non helical) still exist at N/C termini
5. procollagen secreted
6. outside cell, propeptides cleaved by COLLAGENASE mature coll.
7. collagen can self assemble into fibrils (types I, II)
8. LYSYL-OXIDASE cross linking increases strength