ECM and Cell Adhesion Flashcards
What is the primary repeating group in a glycosaminoglycan?
glucuronic acid and N-acetylglucosamine
Do GAGs locate on cell membrane?
Yes. Many GAGs can be found on the extracellular side of the the membranes and can signal cell function as well as interact with surroundings.
What is the general structure and function of a proteoglycan?
PG are covered in GAGs, the Gags are constructed of varying disaccharide combinations (Heparin, Heparan, Dermatan, Condroitin) which can then bind and hold different molecules. They create morphogen gradients by differentially binding growth factors that encourage the development of certain tissues. Some GFs can be bound and active, others are bound an inactivate and must be activated by cells. Creates great variability and control.
What are selectins and how do leukocytes use them?
Endothelial cells display many GAGs in the capillaries. These GAGs are recognized by selectins on leukocytes and allow the leukocyte to slow down from the speed of the blood and exit through the endothelial cells. Specific selectins recognize specific GAGs
What is unique about the binding of selectins and GAGs?
The binding of selectins and GAGs shows both high association constants and high dissociation constants. This means that the proteins bind strongly, but also dissociate quickly. This helps leukocytes slow down in the blood.
How are cancer cells similar to leukocytes?
When they metastasize, the cancer cells must undergo the same “slowing” in the blood stream that leukocytes do. Thus, they must find the GAGs with which their selectins will bind. This makes the cells tissue selective, and explains why breast cancer cell my metastasize bone and not other types of tissues.
What creates the variability in collagen structures including log rope-like structures and network structures?
The crosslinking of the filaments determines the final structure of the collagen. Collagen 1 generally forms rope-like structures, collagen 4 forms networks and is found in the basal lamina.
What is the primary role of fibronectin and laminin?
They are signaling molecules that sit in the ECM and possess multiple binding domains that different cells or structures can bind to.
What are the binding domains of fibronectin and how do they interact with cells?
Fibronectin contains self-association, collagen binding, cell binding, and heparin binding domains. Self associtaion domains allow fibronectin to form networks. Collagen binding domains allow it to fix its position in the ECM. Cell binding domains (Arg-Gly-Asp) allow it to bind with integrins from cells. Heparin binding domains allow it to bind signaling molecules.
How do cells move through the ECM?
Cells bind to fibronectin or laminin, usually with very high specificity (due to integrins). They can navigate their way through the ECM by binding a series of these molecules. This is very important in development, as cells may follow one specific path to a specified location. In adults, immune cells and cancer cells will also move through these pathways.
How do cells move through dense connective tissue such as the basal lamina/basement membrane?
Through the use of podosomes/invadopodia. Invadopodia are actin rich structures. The src gene/kinase is associated with invadopodia activation, as well as the release of matrix membrane proteases (MMRs).
What MMPs are important to know?
MMP 29 and MMP 14 are specific for collagen IV. These two MMPs are upregulated in aggressive, metastatic cancers because they can cut through the basal lamina. Cleavage of Collagen IV and associated GAGs may activate inactvated growth signals on the GAGs, which may stimulate cell growth or movement, creating a positive feedback loop.
What is the basic structure of an integrin?
Integrins are dimers of alpha and beta integrin, and different pairing of types of a & b units creates specificity. Beta 1 binds to firbronectin, other betas may bind to other ECM molecules. Alpha integrin is cleaved and reattached through a disulfide bond. N-terminals bind to ECM when the integrin is dimerized. The Beta-integrin binds to actin inside the cell with its C-terminal. The alpha unit is able to trigger internal cell signals. Integrins cluster at focal adhesion sites.
Why is it remarkable that cancer cells can survive in solution?
Most normal cell must be bound to ECM in order to survive. If the integrin proteins are not bound to ECM, they trigger the caspase 8 apoptosis pathway (extrinsic pathway). Cancer cells that have activated src can survive in solution because the src protein blocks the integrin-caspase 8 pathway.
What is the basic structure of cadherin molecules and junctions?
Cadherin molecules extend from the intracellular space, through the membrane, into the extracellular space. They must dimerize and bind Ca2+ in order to connect with cadherins from the neighboring cell in an antiparrallel fashion.
Do cadherins connect directly to actin inside the cell?
No. They connect to actin through a series of other proteins. They may also bind to microtubules via p120 catenin and beta-catenin. This is another consequence of b-catenin mutation in cancer cells. Without functional b-catenin, cadherins cannot bind to the cyroskeleton and this weakens cell-cell junctions and allows them to disengage from cells around them.
