ECM Flashcards
How the ECM assists in the function of a multicellular organism?
- Stabilizes the physical structure of cells
- Molecular barrier to cell migration during infection and metastasis
- Provides signals to the cell interior during morphogenesis
- Wound healing
- Maintenance of the differentiated state
The ‘reinforcing fibers’ of the ECM?
Collagen
Elastin
Keratin (in hair and nails)
What components make up the ‘hydrated gel’ in which cells and reinforcing fibers are embedded?
Proteoglycans (in most tissues)
Role of…
- Fibroblasts
- Chondrocytes
- Osteoblasts
Synthesize ECM after…
- Wound healing
- Formation of cartilage
- Formation of bone
What ‘holds’ the cells in the ECM?
The multi-adhesive matrix proteins
Fibronectin, laminin, thrombospondin, entactin, etc.
Proteoglycan vs. glycosaminoglycan?
PGs = consist of one or more GAGs covalently attached to a core protein
Hyaluronic acid
And example of the fact that not all GAGs are also PGs…
Since it does not covalently attach to a protein
Proteoglycan aggregate in cartilage…
What happens to it during osteo-arthritis? (OA)
Aggrecan binds to hyaluronic acid via a link protein —> required for proper cartilage function
Proteolytic cleavage of the aggrecan core protein by matric metalliproteases (MMPs) and multidomain extracellular protease enzymes (ADAMTS) —> release the fragment carrying the GAG molecules from the PG aggregate
This loss of the GAG component —> makes the cartilage lose its self-lubricating properties —> OA
Perlecan
PG important for glomerular filtration
Decorin
PG used for controlling the size of collagen fibrils
Aggrecan
PG found in cartilage
Mechanical support, forms large aggregates with hyaluronic acid…
Binds TGF-beta
A multi-adhesive protein?
Usually large secreted protein that has binding sites for both ECM components and a receptor on the cell surface
Fibronectin…location? And to what matrix molecule does it bind?
Found in loose connective tissue and provisional wound matrices
Binds to type I collagen fibrin, heparan sulfacte proteoglycan, and membrane intercolated integrins
An isoform of FN also circulates in the plasma
Laminin-1
Location and what does it bind to?
Multi-adhesive matrix protein found in the basement membrane
Binding sites for type IV collagen, sulfated lipids, and carbohydrates (primarily heparan sulfate) and integrins
Protein important for neuronal development?
Laminin
Protein important in muscular distrophy?
Laminin
Protein important in wound healing
Fibronectin
Which cell adhesion molecules mediate interactions between the same cell types?
Cadherin and CAMs
What types of cell adhesion proteins are utilized in the process of leukocyte extravasation
Selectins and integrins
Why would an agonist that increases cell adhesion prevent leukocyte extravasaction and subsequent inflammation?
The cells bind to tightly that they cannot release to crawl between the endothelial cells
Structure of activated vs inactivated integrin?
Inactive = folded up…therefore cannot bind to ECM molecules nor transduce signals
Active = ‘unfurls’ to expose a ligand binding site…cytoplasmic domains also disengage from each other and can now transduce signals
Integrin presence and function?
Based on the fact that a cell tests postive for beta1 and alpha2 integrin chains
It MIGHT bind to collagen…since alpha2beta1 integrin has that specifity
HOWEVER…
Since the beta1 chain can also interact with a large number of other alpha subunits…additional experiments would be required to confirm this
What intracellular signaling pathway can be activated by integrin ligation?
PI3 kinase pathways (many effects in the cell)
Rho/Rac/cdc42 pathways (primarily cytoskeletal reorganization)
ERK/MAPK pathways (primarily cell proliferation)
Clostridium bacteria (gas gangrene)
Express type IV collagenases to allow invasion deeper into tissues
Cancers can do the same thing
Function of the hydrated gel
Absorb and retain water for lubrication
Charge of GAGs and what that allows them to do
They are negatively charged and highly polar
Allows them to attract/absorb water —> useful to the body as a lubricant and shock absorber
Duchenne vs. Becker muscular dystrophy?
Duchenne = absence of expression of dystrophin protein in cytosol
Becker = lower expression/less functional dystrophin protein
Dystrophin protein
Holds cytoskeleton plasma membraneECM
Important with muscle cells b/c they expand and contract so much
Alpha-beta-dystroglycan
Member of the sarcoglycan membrane complex…which helps connect the internal cytoskeleton to the ECM
Specifically…connect laminin matrix proteins in the basal lamina of muscles
Cadherin
What it binds to =
Location =
Function =
- Cadherin
- Desmosomes
- Mediate adhesion between cells during development (allowing tissue formation)
NCAM
What it binds to?
Location?
Function?
- NCAM
- Neurons and muscle
- Neuronal development and have a similar structure to immunoglobulin molecules
Integrin
What it binds to to
Location
Function
- Fibronectin
- Multiple cell types
- Allows communication across the plasma membrane…interacts with cytoskeleton
Selectin
What it binds to
Location
Function
- Glycoprotein
- WBCs and endothelial cells
- Movement of WBCs (extravasation)
Resting state in the extravasation process…
Resting state=
selectin ligand is actively expressed
Alpha-L-beta-2 integrin is inactive
P-selectin molecule is within vesicles in the endothelial celsl
After injury is detected in tissue (extravasation) —>
- Platelet activating factor (PAF) released —> P-selectin released
- When P-selectin is loosely attached to the selectin ligands —> leukocyte starts to ‘roll’ towards the affected tissue
- Leukocyte is now activated and the released PAF goes on to activate alpha-L-beta-2 integrin molecule on the leukocyte
- Alpha-L-beta-2 integrin molecules bind with ICAM molecules on endothelial surface…and PAF (on endothelial surfaces) binds to PAF receptor (on leukocyte)
- Integrin/ICAM interaction allows the WBC to migrate through the endothelium into the underlying tissue to increase inflammation
Multiple sclerosis
When the immune system attacks myelin within the CNS and causes hyper-inflammation within the body
Natalizumab
Antagonistic drug therapy for MS
Binds to alpha-L-beta2 integrin subunit
Allows WBC to keep rolling through blood vessel without resulting in immune system destruction
MS agonist drug therapy
ALB2 integrin agonist binds to WBC so tightly to the integrin molecule that it cannot move into the cell
Biggest reduction of inflammation but can cause immune system destruction
Role of integrin
Play huge role in cell cycle regulation…
Obligate heterodimer (type of CAM)
Binds to fibronectin
