Flashcards in Extracellular Matrix and Cell Adhesion Deck (28)
1. Discuss the contributions of the ECM to cell and tissue function.
2. Define the four major classes of ECM components and their properties.
3. Define two types of fibrillar proteins and at least two types of multidomain adapter proteins of the ECM.
4. Discuss the role of MMPs in ECM remodeling.
5. Discuss the role of adhesion in cell function and survival.
6. Define and describe at least three different types of cell adhesion molecules (CAMs) and their ligands.
7. Discuss the role of CAMs in signaling.
8. Describe proteins associated intracellularly with CAMs.
9. Discuss the ECM and cell adhesion in the context of disease processes.
ECM is non-cellular excreted material
Define the four major classes of ECM components and their properties.
1) glycosaminoglycans (GAGs) [proteoglycans]
2) fibrous proteins [collagen, elsastin]
3) multidomain adapter proteins [fibronectin and laminin]
4) water and many solutes
Discuss the contributions of the ECM to cell and tissue function.
Most mammalian cell types, adhesion to other cells or the extracellular matrix (ECM) is critical for cell survival [not cancer cells]. Relative amount of ECM dependent on tissue type [connective vs neural, for example]
Cell adhesion is specific and selective [fibroblasts only grown on fibronectin].
The ECM serves not only as a scaffold for cells but also participates in regulating various cell functions (survival, differentiation, migration, proliferation, and shape).
ECM cells made by members of the fibroblast family [chondroblasts, fibroblasts, depending on tissue type]
What are two fibrillar proteins?
What are two multidomain adapter proteins?
What are MMPs?
[extracellular proteases secreted to turn over the ECM; particularly important in tissue remodeling during development and in cell invasion of tissues]
What is the significance of cell adhesion molecules?
Cell adhesion molecules are not simply adhesive devices: For adhesion and force generation against the ECM or other cells, they form a trans-membrane link with the cytoskeleton. When bound to a ligand, CAMs signal their engagement via conformational change to the cell interior, thus affecting cell function.
Define and describe at least three different types of cell adhesion molecules (CAMs) and their ligands.
1) Cadherins [bind other cadherins = homophilic]
2) Ig Superfamily (IgSF) CAMs [homophilic]
3) Integrins [bind ECM]
Discuss the role of CAMs in signaling. Describe proteins associated intracellularly with CAMs.
In addition to providing the cytoskeletal link, CAM-associated proteins also are involved in the regulation of adhesion, in the control of actin polymerization, and in cell signaling mediated by CAMs. For example, assembly of adhesion sites requires the action of protein tyrosine kinases, whereas disassembly and detachment appears to require protein kinase C activity. Members of the Rho family of small GTPases involved in the regulation of F-actin polymerization (see Cell Motility) also are associated with certain CAMs. It follows that CAMs are paired on the cytoplasmic face of the membrane with complex protein assemblies that serve mechanical, controlling, and signaling functions. It is not surprising, therefore, that these adhesion sites play major roles in cell differentiation/development and cancer. In development, CAMs change as cells differentiate.
_____ mutations are relatively frequent. They interfere with osteogenesis and cause skeletal dysplasias.
_____ null mutant mice are early embryonic lethal.
[Because of the severe consequences (developmental and other) loss-of-function of a CAM may result in embryonic lethality (see fibronectin, above).]
Some ______ mutations have been linked to nephrotic syndrome (glomerular filtration defect) and to neuromuscular junction/muscle innervation problems in children.
Loss-of-function mutations of ______ cause inherited osteolysis/arthritis syndromes and bone dysplasias.
matrix metalloproteases (MMP) 2 or 13
Overexpression of some MMPs, specifically (3), correlates with high invasiveness and poor prognosis in many cancers.
MMP2, MMP9 and MMP14
Two types of leukocyte adhesion deficiencies have been identified:
- Type I, affecting a particular integrin.
- Type II, affecting a selectin, a CAM involved in leukocyte rolling (the initial contact with vascular endothelial cells, prior to adhesion and extravasation).
Cancer(1): One of the early signs of carcinogenesis is a change in ____. This is accompanied by (and may be the reason for) perturbed cell polarity and cytoarchitecture.
Cancer(2): _____ down-regulation appears to be a prerequisite for the dispersal of epithelium-
derived cancer cells.
Cancer (3): Anchorage independence of cancer cells results from mutations in proteins of the _____.
signaling apparatus associated with cell adhesions
Cancer(4): Certain ____ are known to be tumor suppressors.
[This means that loss of catenin function promotes carcinogenesis.]
Glucosaminoglycans (GAGs). What are they. What is your personal experience with one? what is unique about that one in particular?
GAGs are polysaccharide chains composed of disaccharide repeats. They have a sulfated amino sugar and uronic acid. The sulfate and carboxyl groups give them a large negative charge which allows hydration. They readily form gels. [hyaluronan, chondroitin sulfate, dermatan sulfate, heparan sulfate and keratan sulfate]
Hyaluronic acid is the only GAG that exists by itself (free of proteins). Usually a very big molecule, used to form fibrous jello-like substance because it gets hydrated.
What are covalently linked complexes of GAGs and protein? What do they do?
Proteoglycans (PGs). Can be HUGE eg aggrecan, and play an important role, e.g., in the filtering function of the kidney glomerulus and as "reservoirs" of growth factors and proteases, which they may bind, and whose activity they may modify.
Play an important role in limiting diffusion of growth factors etc to maintain gradients.
Describe the phenomenon of leukocyte rolling.
Circulating leukocytes have to extravasate out of a capillary from the blood. Endothelial cells express GAGs, which have an affinity for Selectins on the leukocyte. [GAGs also accumulate chemokines which signal the Leukocytes]
Selectin/GAG have high binding constant AND a high disassociation constant. attx/letgo/attx/letgo happens really fast, acts as brakes. Leukocyte slows down and exits capillary.
Collagens are fibrous proteins and the most abundant proteins in mammals (about 25% of protein mass). About 25 distinct collagen subunits have been identified. They are known to assemble into about 20 different collagens. ______ is the most common form, abundant in connective tissues (see Connective Tissue). _____ is characteristic of the basal lamina.
Collagen I; Collagen IV
[can be ropelike or sheetlike, all are built from cross-linking]
[procollagen---secreted in huge vesicle--> tropocollagen ---> cross linking to form collagen]
Signaling molecules are a very small proportion (by far the majority is GAG and collagen). What are two?
fibronectin and lamin.
Podosome = invadopodia
Form in many contexts, but often refers to epithelial cancer cells. Make a "snout" that can intravasate through the basement membrane.
[Invadopodia are induced by src.]
MMP2, MMP9 and MMP14 are very specific to ______.
Collagen 4. These allow cancer cells to breach the basement membrane [each MMP is specific to a certain tissue type]
What small molecule is required for cadherin to function?
Ca2+ [needed to dimerize and then bind to neighboring cadherin on next cell]