Cell Adhesion Flashcards
Cadherins function
- Probably the most important class of proteins that mediate cell to cell attachment
- Binding requires Calcium
- Mediate homophilic (like to like) adhesion
* Binding probably occurs at the N-terminal tips
Intracellular domains of cadherins provide anchorage for what filaments of the cytoskeleton?
- Linkage to cytoskeleton is indirect
*Depends on intracellular anchorage proteins that assemble on the tail of the cadherin
*Beta-catenin plays a central part
- Anchorage to actin at adherens junctions
- Intermediate filaments at desmosome junctions
2 classes of Cadherins
- Classical Cadherins
- Non-classical Cadherins
Classical Cadherins and their location
- All closely related to each other
*N-cadherin: form adherens junctions and chemical synapses of nerve, muscle, skeletal fibroblasts and lens cells
*P-cadherin: form adherens junctions of cells in the placenta, epidermis and breast epithelium
*E-cadherin: form adherens junctions of many types of epithelial cells
Non-classical Cadherins and their location
- More distantly related in terms of sequence
- Include proteins w/ adhesive properties
*Protocadherins: expressed in brain
*Desmocollins/Desmoglein: form desmosomes in skin; phenotype when inactivated = Blistering of skin (blistering skin disease due to loss of keratinocyte cell-cell adhesion (Desmogloein))
*Proteins w/ signalling function; T-cadherin: expressed in nerve and muscle cells
Cadharin adhesion
- Mediate homophilic adhesion
- Binding probably occurs at N-terminal tips
*Protein knob and pocket structure
Integrins function
- Coordinate or integrate signals from extracellular ligands with cytoskeleton-dependent motility, shape change and phagocytic responses
- About 30 structurally homologous proteins that promote cell-cell or cell-matrix interactions
- Heterodimeric cell surface proteins that are composed of two covalently linked polypeptide chains alpha and beta
- Alpha and beta extracellular chains bind to various cytoskeletal components including ligands, and extracellular matrix proteins (ECM) glycoproteins
- 2 classes
*Beta-1 integrins
*Beta-2 integrins
Integrin extracellular domains functions
- Activate complement components
- Several integrins bind to arg-gly-asp (RGD) sequences in fibronectin and other ECM glycoproteins
*Fibronectin: ECM protein involved in adhesion of cells to matrix
- Important in movement of cells during embryogenesis
- Some integrins bind to other cells
Integrin intracellular/cytoplasmic domains interact with what cytoskeletal components?
- Talin: intracellular anchorage protein
- Actin: major constituent of actin filaments (major component of the cytoskeleton)
- Tropomyosin: protein involved in the stabilization of actin filaments
- D-actinin: bundling protein
- Vinculin: membrane-cytoskeletal protein in focal adhesion plaques
Beta-1 Integrins
- 3 integrin families
- Also called VLA molecules (very late activation) because they are expressed on T-cells after 2-4 weeks of repetitive stimulation in vitro
*VLA4: one of the principal surface proteins that mediate homing of lymphocytes to endothelium at peripheral sites of inflammation
Beta-2 Integrins
- Also called LFA-1 family (lymphocyte function associated antigen)
- Plays an important role in the adhesion of lymphocytes and other leukocytes with other cells such as APC’s and vascular endothelium
*CD11bCD18 (MAC-1 or CR3) *CD11cCd18 (p150, 95 or CR4)
CD11bCD18 (MAC-1 or CR3) and CD11cCd18 (p150, 95 or CR4) functions
- Beta-2 Integrins
- Both mediate leukocyte attachment to endothelial cells and subsequent extravasation
- Expressed on T-cells
*LFA1 integrin has weak binding with the ICAM receptor on APC’s (Immunoglobin superfamily protein)
* Antigen recognition by T-cell receptor w/ the MHC protein on the APC sends signal to activate LFA1 integrin
*LFA1 integrin binds more strongly to ICAM
- CD11bCD18 (MAC-1 or CR3) also functions as a fibrinogen receptor and as a complement receptor on phagocytic cells
Selectins function
- Selectins are cell surface carbohydrate-binding proteins (lectins)
*Single chain transmembrane glycoproteins w/ an amino terminus that is related to carbohydrate-binding proteins called C-type lectins
*Binding is calcium dependent
- Mediate transient cell-cell adhesions in the bloodstream
Selectins 3 types
- L-selectin
- P-selectin
- E-selectin
L-selectin location
- Expressed on white blood cells (lymphocytes and other leukocytes)
*Located at the tips of microvillus projections of leukocytes facilitating its interaction with ligands on endothelium
L-selectin functions
- Major function: homing receptor for lymphocytes to enter lymph nodes by binding to high endothelial venules
- Minor function: facilitates binding of neutrophils to cytokine-activated endothelial cells at sites of inflammation
Endothelial ligands that can bind to L-selectin
- GlyCAM-1
*(glycan-bearing cell adhesion molecule 1): secreted proteoglycan found on HEVs of lymph node
- MadCAM-1
*(mucosal addressing cell adhesion molecule 1): expressed on endothelial cells in gut associated lymphoid tissue
- CD34
*A proteoglycan found on endothelial and bone marrow cells
- Protein backbones of all these ligands are modified by specific carbohydrates which are the molecules actually recgonized by the selectin
E-selectin location
- Expressed on cytokine activated endothelial cells
*Endothelial expression of E-selectins is the hallmark of acute cytokine mediated inflammation
E-selectin functions
- Important in the homing of effector and memory T-cells to some peripheral sites of inflammation, particularly in the skin
- Recognizes complex sialylated carbohydrate groups
- Hallmark of acute cytokine mediated inflammation when expressed on endothelial cells
P-selectin location
- Platelets and activated endothelial cells in an inflammatory response
- Also found in secretory granules of endothelial cells (Weibel-Palade bodies)
P-selectin function
- When platelets or endothelial cells are stimulated, P-selectin is translocated within minutes to the cell surface
- Mediates binding of neutrophils, T-lymphocytes and monocytes
Immunoglobin superfamily function
- Represent the major endothelial proteins recognized by the integrins
- Contain one or more of the extracellular globular domains that are characteristic of immunoglobin molecules
Immunoglobin superfamily endothelial adhesion molecules
- ICAM-1 (intercellular adhesion molecule-1)
- VCAM-1 (vascular cell adhesion molecule-1)
*Both ICAM-1 and VCAM-1 serve as ligands for integrins found on leukocytes
- NCAM (expressed on multiple cell types, including neural cells)
Loss of cadherins effects
- Can lead to a malignant phenotype
- Allows easy disaggregation of cells
- Local invasion
- Distant metastasis
Reduced cell surface expression of E-cadherin effects
- Noted in cancers of:
*Esophagus
* Breast
*Colon
*Ovary
*Prostate
Beta-catenin role in cancer
- Subunit of the cadherin protein complex and acts as an intracellular signal transducer in the Wnt signaling pathway
*WNT signaling pathway has major role in controlling fate, adhesion and polarity of cells during development and is also important in hematopoiesis
- In the absence of WNT signaling, APC forms a complex w/ other proteins and degrades Beta-catenin, thus preventing its accumulation in the cytosol
*APC represents a class of tumor supressor genes whose main function is to down-regulate growth promoting signals (particularly Beta-catenin)
*If APC is deleted, there is no degradation of Beta-catenin and cell proliferation is unchecked
- When WNT binds to its receptor, this destruction complex is blocked
*This allows Beta-catenin to move to the nucleus, where it complexes to a transcriptional factor that up-regulates cell proliferation
- Mutations in Beta-catenin present in 50% of hepatoblastomas and 20% of hepatocellular carcinomas
APC mutations in cancer
- APC represents a class of tumor suppressor genes whose main function is to down-regulate growth promoting signals
- Germline mutations in APC are associated w/ familial adenomatous polyposis
*Individuals born with one mutant allele develop thousands of polyps in the colon in late teens/early 20’s
*Colon cancer: one or more of these polyps undergoes malignant transformation, which is associated with loss of both APC copies
*70-80% of non-familial colorectal carcinomas and adenomas also have loss of both APC copies
