Cellular Adhesion Flashcards
What are the 2 basic strategies for holding cells together
- Extracellular Matrix
2. Cytoskeleton strength/cell-cell adhesions (tie cytoskeletons of neighboring cells together)
Name 4 types of cellular junctions
- Tight Junction
- Adherens Junction
- Desmosome
- Gap Junction
What is the purpose of a gap junction?
To seal gaps between epithelial cells
What is the purpose of adherens junction?
To connect actin filament bundles in one cell to that in the adjacent cell
What is the purpose of the desmosome?
To connect intermediate filaments in one cell to that in the adjacent cel
What is the purpose of the gap junction?
To allow the passage of small water soluble molecules from cell to cell
What are the adhesion proteins for the adherens junction and desmosome called?
Cadherins
- Adherens junction has classical cadherins
- Desmosome has nonclassical cadherins
There are 2 anchoring junctions to connect the cell to the matrix, what are they? Also name the corresponding transmembrane adhesion protein.
- Actin-linked cell-matrix junction (Integrin)
2. Hemidesmosome (alpha/beta Integrin, XVII collagen)
What are the 4 types of adhesion molecules?
- Integrins
- Cadherins
- Selectins
- Immunoglobulins
What are the 3 types of nonclassical cadherins and on what cell types or body structures are they found?
- N-cadherin: nerve, muscle, and lens cells
- P-cadherin: placenta and epidermis
- E-cadherin: many types of epithelial cells
What are the 3 non-classical cadherins with adhesive properties and 1 with signalling function? Where are they found?
Adhesive Properties 1. Protocadherins: Brain 2. Desmocollins 3. Desmogleins (both form desmosome junctions) Signalling Function 1. T-cadherin: nerve and muscle cells
If there is a problem with either desmocollin or desmoglein where in the body will the phenotype be observed and what will be observed?
Blistering of the skin
Through what interactions do cadherins mediate cell to cell adhesion?
Homophillic interactions where specific cadherins on one cell bind to the same (or closely related) cadherins on a second cell
Describe the structure of the cadherin and the model by which they interact with one another.
Structure: N-terminal cadherin repeat, flexible hinge region, and a calcium binding motif
Model: Protein knob and pocket structure
Binding is low affinity
What 2 things does the spacing between cells depend on when anchoring is via cadherin?
- Type of cadherin expressed (some have different lengths)
2. Strength of interaction (the more cadherins the stronger the interaction)
Cadherins are transmembrane proteins that interact with other cadherins on their extracellular domain. What does their intracellular domain interact with?
Interacts with the cytoskeleton but indirectly because there are anchorage proteins that bridge the cadherin to the actin (if adherens junction) or intermediate filaments (if desmosome)
What is one of the most important anchorage proteins that interacts with cadherin and has been implicated in colon cancer?
Beta-catenin
Cadherins, when lost or dysfunctional, have been implicated in malignant and cancerous phenotype. What are 3 reasons for this? E-cadherin specifically has been noted in what 5 types of cancer?
Loss of cadherins
- Allows for easy disaggregation of cells
- Local invasion
- Distant metastasis
E-cadherin is associated with
- Esophagus
- Breast
- Colon
- Ovary
- Prostate
E-cadherin aside from somatic mutations is also associated with germ line mutations which can cause a person to be predisposed to what condition/disease?
Familial Gastric Carcinoma
Beta catenin aside from being an anchorage protein is also involved in what cellular process?
Cell cycle regulation: specifically it upregulates it, causing cell proliferation
Adenomatous polyposis coli (APC) is a protein which is a tumor suppressor. What is it’s function and how does it achieve this?
Function: Down-regulate growth promoting signals
Achieved: APC binds to beta-catenin and degrades it
Through what receptor does beta-catenin become activated? How does this work?
WNT receptor: receives a signal and causes APC to get degraded. This means that APC can no longer degraded beta-catenin which can cause the cell to proliferate
APC has been implicated in what two types of cancers?
Colon and Liver
What do selectins bind? What broader class of proteins do they represent? Where is this binding found in the body? And what is the binding dependent upon?
Selectins bind carbohydrate moieties
The are part of the lectin family of proteins which are cell surface carbohydrate binding proteins
Binding is transient and found in the bloodstream
Binding is calcium dependent
What are the 3 types of selectins and where are they found?
- L-selectin: WBCs
- P-selectin: platelets and activated endothelial cells in an inflammatory response
- E-selectin: activated endothelial cells
What is the major and the minor role of L-selectin?
Major role: homing receptor for lymphocytes to enter secondary lymphoid tissue by binding to high endothelial venules (HEVs)
Minor role: facilitate binding of neutrophils to cytokine-activated endothelial cells at sites of inflammation
Where is L-selectin found specifically on WBCs?
At the tip of the microvillus projection
What are the 3 main endothelial ligands that bind L-selectin and on what cells/body structures are they expressed?
- GlyCAM-1: HEV of lymph node
- MadCAM-1: endothelial cells in gut associated lymphoid tissue (GALT)
- CD34: endothelial cells and bone marrow cells
What L-selectin ligands allow for the extravasation of lymphocytes into lymph?
GlyCAM-1 and CD34
What type of ligand does E-selectin recognize and what 3 cell types are the ligands found on?
Recognizes complex sialylated carbohydrate groups related to the Lewis A or Lewis X family.
Ligands are found on surface proteins of granulocytes, monocytes, and previously activated effector and memory T cells
Endothelial expression of E-selectin is associated with what process?
Acute cytokine mediated inflammation
Where in endothelial cells is P-selectin found?
Secretory granules known as Weibel-Palade bodies
What 3 cell types does P-selectin mediate binding of?
- Neutrophils
- T Lymphocytes
- Monocytes
P-selectin is stored in Weibel-Palade bodies in the cell. How does it exert it’s extracellular effect?
Platelets or endothelial cells become stimulated by cytokines which cause translocation of the Weibel-Palade body to fuse with the cell membrane thus causing P-selectin to be exposed to the bloodstream
What are the effects, in mice, of each of the selectins if they are defective or deficient?
Deficiencies in….
L-selectin cause small lymph nodes with few T cells
P or E-selectin cause mild defects in leukocyte function
In humans the deficiency is not in the selectin but rather the ligand which causes a problem. Humans who lack enzymes to express ligand for either P or E-selectin in neutrophils suffer from what condition?
Leukocyte adhesion deficiency 2 which causes a person to suffer from recurrent bacterial infections
Integrins get their name from the hypothesis that they _______________?
Coordinate or integrate signals from extracellular ligands with cytoskeleton-dependent motility, shape change, and phagocytic responses
Unlike cadherins, integrins exist as what kind of complex?
Heterodimer (composed of 2 noncovalently linked polypeptide chains called alpha and beta)
The extracellular domain of the integrin heterodimer binds what?
Various ligands but most specifically extracellular matrix proteins/glycoproteins
Aside from mediating cell to cell or cell to matrix interaction what other function do integrins have?
They activate complement components
Several integrins bind to what 3 amino acid motif found in what specific protein?
Bind to an arg-gly-asp (RGD) sequence found in fibronectin and other ECM glycoproteins
What is the function of fibronectin?
Mediates adhesion of cells to matrix and during embryogenesis it is important for movement of cells
The cytoplasmic domain of integrin interacts with what 5 things?
Interacts with cytoskeletal components, specifically….
- Talin (intracellular anchorage protein)
- Actin
- Tropomyosin (stabilizes the actin filaments)
- alpha-actinin (bundling protein)
- Vinculin (membrane-cytoskeletal protein found in focal adhesion plaques)
Under what conditions and what cell type would we be likely to find beta-1 integrins? What is another name for them?
Also called “very late activation (VLA) molecules” they are found on activated T cells after 2-4 weeks of repetitive stimulation in vitro.
Also called CD49a-g (depending on what alpha chain is attached)
Another B1 integrin is VLA4 (alpha-4, beta-1). What is its function?
Mediates homing of lymphocytes to endothelium at peripheral sites of inflammation
One of the three members of the B2 integrins is LFA-1 (CD11aCD18). What is its function?
Adhesion of lymphocytes and other leukocytes to APCs and vascular endothelium
CR3 (CD11bCD18) and CR4 (CD11cCD18) are the other two members of the B2 integrins. What is their function?
Leukocyte attachment to endothelial cells and subsequent extravasation.
CD11bCD18 is a fibrinogen receptor and complement receptor on phagocytic cells which responds to inactivated C3b (iC3b) fragment
B2 integrin LFA-1 (CD11aCD18) is expressed on T cells, what does it interact with on the APC?
Binds to ICAM. The LFA-1/ICAM interaction functions as a coreceptor (it’s the handshake the T cell needs)
Defects in integrins result in what condition?
Leukocyte adhesion deficiency 1, which is a failure to synthesize B2 chains. This leads to repeated bacterial infections
What are the 3 endothelial adhesion molecules that are members of the immunoglobulin superfamily?
- ICAM-1
- VCAM-1
- NCAM (found on multiple cells types including neural cells)
