cellular adhesions – Flashcards
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| what are the 2 basic strategies for holding cells together? |
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| the strength of the extracellular matrix, the strength of the cell cytoskeleton inside/the strength of the cell-cell adhesions tying the cytoskeletons of adjacent cells together |
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| what is the extracellular matrix? |
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| a complex network of proteins and polysaccharide chains secreted by the cells |
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| what are the 4 types of cellular junctions? what do they do? |
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| anchoring junctions, (cell-cell adhesions/cell-matrix), occluding junctions, (seals gap between cells in epithelia), channel-forming junctions, (passageways created between cytoplasm of cells), and signal relaying junctions, (relay chemical synapses in nervous+immune systems) |
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| what is metastasis? |
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| the ability of a cell to break free of its neighbors and settle somewhere else+divide |
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| what are the classes of adhesion molecules? |
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| cadherins, selectins, members of the immunoglobulin superfamily, and integrins |
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| what are cadherins? |
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| important class of proteins for mediating cell-cell attachments, their name is derived from Ca dependence in binding |
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| what are the classical cadherins? |
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| N-cadherin - nerve/muscle/lens cells, P-cadherin - placenta/epidermis, E-cadherin - many epithelial cells. expression is not however limited to these cell types. they are also closely related to each other in intracellular and extracellular domains. |
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| what are protocadherins, desmocollins, desmogleins, and T-cadherins? |
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| non-classical cadherins. protocadherins are located in the brain, (50+ non-classical cadherins in brain alone), desmocollins and desmogleins form desmosome junctions, and T-cadherins have signalling functions in nerve and muscle cells. |
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| how are non-classical cadherins different from classical? |
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| they are more distantly related in terms of sequence. |
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| what defines classical cadherins? |
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| classical cadherins are probably the most important proteins in adhering like cells, (homophilic adhesion), b/c they only like to bind to other cadherins of the same type. |
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| what is Ca's involvement in cadherins? |
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| the proteins are long, and end up being "wobbly" w/out Ca. Ca helps them to remain rigid by binding to the "hinge region" of the protein. |
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| how tight are individual cadherin bonds? |
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| individual cadherin binding is low affinity, the strength of these functionally is in numbers, (like velcro) |
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| what does the type of cadherins involved dictate concerning cell-cell anchoring junctions? |
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| the spacing between cell membranes is tightly definted by which cadherins are expressed |
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| how do the intracellular domains of cadherins work? @ adherns junctions? @ desmosome junctions? is the linkage direct? what does the type of adaptor protien is used in anchorage depend on? |
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| at adherns junctions, anchorage is to actin, at desmosome junctions, anchorage is to intermediate filaments. these linkages are almost always indirect, and depend on the intracellular anchorage proteins assembling on the tail of the cadherin. in general, beta-catenin plays a central part. |
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| what can loss of cadherins lead to? how? |
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| loss of cadherins can lead to a malignant phenotype via easy disaggregation of cells, local invasion, and distant metastasis |
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| which cancers is reduced surface expression of E-cadherin noted in? |
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| cancer of the esophagus, breast, colon, ovary, and prostate |
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| germ line mutations of which cadherin can predispose one to familial gastric carcinoma? |
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| E-cadherin |
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| what is beta catenin? what are 2 roles does it play in the body? |
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| beta catenin is an element of the anchoring complex between cadherins+cytoskeleton. beta catenin is also a gene regulatory protein that promotes cellular proliferation. |
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| what is APC? what are germline mutations in APC associated with? |
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| APC, (adenomatous polyposis coli), is a tumor suppressor gene whose main function is to down-regulate growth promoting signals, such as beta catenin. germline mutations in APC are associated with familial adenomatous polyposis, (people w/this develop 1000s of colon polyps in late teens/early 20s) |
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| how do APC and beta catenin interact? |
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| APC binds to beta catenin, forming a destruction complex, and beta catenin is unable to promote cell proliferation. however, if something called the WNT receptor on a cell is activated, the destruction complex between APC and beta catenin is disrupted and beta catenin promotes cell proliferation |
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| what happens if there is a mutation in one APC gene copy, what if both are mutated/lost? why? |
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| one lost APC copy will result in polyps, loss of two APC gene copies is associated with malignacy. this occurs b/c APC is not present to bind beta catenin, and cell proliferation continues unchecked. 70-80% of non-familial colorectal carcinomas are affected by this disfunction. |
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| can mutations in beta catenin also lead to malignacy? |
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| yes, they are associated with 50% of hepatoblastomas and 20% of hepatocellular carcinomas |
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| what are selectins? what are they composed of? is their binding dependent on anything? |
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| selectins are cell surface carbohydrate binding proteins, (lectins). they are all single chain, transmembrane glycoproteins w/an amino terminus related to carb binding proteins called C-type lectins. their binding is Ca-dependent |
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| what do selectins do? |
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| they mediate transient cell-cell adhesions in the bloodstream |
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| what are the 3 kinds of selectins and where do they bind? |
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| L-selectins, found on WBCs, (lympho/leukocytes), P-selectins, found on platlets+activated endothelial cells in inflammatory responses and E-selectins, found on activated endothelial cells |
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| what is the major function of L-selectin? |
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| MAJOR function: homing receptor for lymphocytes to enter lymph nodes by binding to high endothelial venules. |
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| what is the minor function of L-selectin? |
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| L-selectin facilitates binding of neutrophils to cytokine-activated endothelial cells at sites of inflammation |
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| where is L-selectin located? |
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| on the tips of microvillus projections of leukocytes facilitating its interaction with ligands on endothelium |
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| how do leukocytes interact with endothelial cells? |
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| "rolling" via microvilli tipped with L-selectin |
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| what are the 3 endothelial ligand that can bind L-selectin? where are they found? |
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| GlyCAM-1, (secreted proteoglycan found on HEVs of a lymph node), MadCAM-1, (expressed on endothelial cells in gut associated lymphoid tissue), CD34, (proteoglycan found on endothelial cells and bone marrow cells) |
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| what do GlyCAM-1, MadCAM-1, and CD34 have in common? |
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| these ligand all have protein backbones modified by specific carbohydrates, which are the molecules actually recognized by the selectin |
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| where is E-selectin expressed, what does it recognize? where are it's ligands found? |
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| E-selectin is expressed on cytokine activated endothelial cells and it recognizes complex sialylated carbohydrate groups, (lewis A or X family). it's ligands are located on surface proteins of granulocytes, monocytes, and previously activated effector+memory T cells. |
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| what is E selectin important in? what is it the hallmark of? |
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| E selectin is important in the homing of effector+memory T cells to some peripheral sites of inflammation, particularly in the skin. endothelial expression of E-selectins is the hallmark of acute cytokine mediated inflammation |
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| where are P selectins found? |
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| P selectins are found in secretory granules of platelets, as well as in Weibel-Palade bodies, (secretory granules of endothelial cells). |
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| what do P selectins do when platelets or endothelial cells are stimulated? |
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| P selectins are translocated within minutes to the cell surface. |
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| what doe P selectins do? |
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| P selectins mediate binding of neutrophils, T lymphocytes and monocytes to platelets/endothelial cells. |
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| what do P and E selectins have in common? |
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| the carbohydrate moieties that both bind appear similar |
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| what happens if L-selectin is knocked ou in mice? |
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| they have poorly formed, small lymph nodes with few T cells |
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| what happens if P and E selectin are knocked out in mice? |
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| they have mild defects in leukocyte function, double knockouts are more severely impaired-> increased risk of infection |
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| what deficiency do humans lacking one of the enzymes needed to express the carbohydrate ligands for E+P selectin in neutrophils have |
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| leukocyte adhesion deficiency II, they have problems expressing acute inflammation |
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| what are integrins? |
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| ~30 structurally homologous proteins that promote cell-cell or cell-matrix interactions. they are thought to integrate signals from extracellular ligands w/cytoskeleton-dependent motility, shape change and phagocytic responses |
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| what does the fact that integrins are heterodimers mean? |
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| they have two noncovalently linked alpha and beta polypeptide chains, (both transmembrane) |
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| what do the extracellular domains of integrins 2 chains bind to? |
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| various ligands including ECM, (extracellular matrix), proteins that activate complement components. several integrins also bind to arg-gly-asp, (RGD), which are sequences in fibronectin, an ECM protein involved in adhesion of cells to the matrix. other. some integrins bind to other cells and ECM glycoproteins. |
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| what do the cytoplamic domains of integrins interact with? |
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| cytoskeletal components, including talin, (intracellular anchorage protein), actin filamens, (major constituent of the cytoskeleton), tropomyosin, (protein involved in stablizing actin filaments), alpha-actinin, (bundling protein), and vinculin, (a membrane-cytoskeletal protein in focal adhesion plaques) |
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| what are the beta-1 integrins? |
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| beta-1 integrins are also called VLA molecules, (very late activation), b/c they are expressed on T cells after 2-4 weeks of repetitive stimulation in vitro. other VLA are constitutively or rapidly expressed. beta-1 integrins are also called CD49a-g, depending on which alpha chain is attached |
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| what is VLA4, (alpha4beta1)? |
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| VLA4, a beta-1 integrin, it is one of the principal surface proteins that mediates homing of lymphocytes to the endothelium at peripheral sites of inflammation |
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| what is another term for beta-2 integrins? |
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| the LFA-1 family or CD11a-c/CD18, (where a-c refers to different alpha chains and CD18 to the common beta-2 chain associated w/each) |
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| what does LFA-1, (CD11aCD18), do? |
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| LFA-1 plays an important role in adhesion of lymphocytes/other leukocytes w/other cells such as APC's and vascular endothelium, (intial contact to dermine if T cell wants the antigen from the APC, will become a tighter connection if the antigen is what the T cell was looking for) |
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| what do CD11bCD18, (mac-1 or CR3) and CD11cCD18, (p150,95 or CR4) do? |
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| these beta-2 integrins mediate leukocyte attachments to endothelial cells and subsequent extravasation. CD11cCD18 specifically functions as a fibrinogen/complement receptor on phagocytic cells, binding particles opsonized w/a complement activation by-product, inactivated C3b fragment, (iC3b) |
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| what does leukocyte adhesion deficiency 1 result in? |
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| a failure to synthesize beta-2 chains, (CD11/CD18 integrins) resulting in repeated bacterial infections -> death is common within 2 years |
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| what do members of the immunoglobin superfamily all contain? |
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| one or more extracellular globular domains, (characteristic of immunoglobin molecules). 2 endothelial adhesion molecules, ICAM-1, VCAM-1, (and sometimes NCAM), which serve as ligands for integrins found on leukocytes |
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| what is one thing integrins bind to? |
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| ICAMs |
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| in terms of leukocytes, what kind of movement are each of these associated with? selectins:______ integrins/ICAMS:_______ |
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| selectins: rolling integrins/ICAMS: stop |
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| what does ICAM stand for? |
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| intercellular adhesion molecule-1 |
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| what does VCAM-1 stand for? |
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| vascular adhesion molecule-1 |
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| what does NCAM stand for? |
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| neural adhesion molecule, but it is also seen on other cell types |
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| what do members of the immunoglobin superfamily represent? |
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| they represent the major endothelial proteins recognized by the integrins |
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| what do chemokines do? |
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| they are released from the PMN after binding to the selectins, they cause the integrins bound to ICAMs to go from low affinity to high affinity states. |
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| what happens when the PMN/leukocyte stops after chemokines have done their job? |
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| the PMN enters the tissue, and becomes part of the acute inflammatory process |
