Advanced Molecular Genetics-Biology 566
Signal Transduction and adhesion molecules
Three levels of contact with environment
Molecules involved in cell adhesion
ICAMs, InterCellularAdhesion Molecules - three subfamilies, ICAM-2 is found on all endothelial cells
NCAM, bind to other NCAMs.
VCAMs, Vascular Cell Adhesion Molecules have two splice variants.
PECAM, Platelet Endothelial Cell Adhesion Molecule (CD31)
"The integrins are the most dynamic and versatile of the adhesions molecules. They are composed of two subunits alpha (12 types) and beta (7 types).
The extracellular chains posses binding sites for divalent cations and depending on the alpha-beta combination they may bind to ICAMs, VCAM-1 or to MadCAM (on mucosal cells). They may also bind to components of the extracellular matrix and to the blood proteins, fibroinogen or von Willebrand Factor."
The cytoplasmic domain of the beta subunits can be phosphorylated and this possibly regulated interaction with cytoskeleton.
Cadherins are specific Ca2+ dependent adhesion molecules that regulate intercellular recognition and are fundamental to the process of animal morphogenesis.
Cadherins generally mediate homotypic cell-cell adhesion and they are present in cell-cell junctions, adherens junctions and desmosomes
"Selectins are present on the surface of white blood cells, platelets and also the cells lining the blood vessels (endithelial cells). They mediate the initial low-affinity adhesion sites for lymphocytes and for leukocytes such as neutrophils. This prepares the way for cell migration into the lumph nodes and tissues."
Little is known about the role of the selectins in signal transduction. However, they have a remarkable property that allows them to modulate their affinity in response to shear forces.
Cartilage link proteins
Hyaluronan is a high molecular weight glycosaminoglycan polysaccacharide (with a repeating unit of D-glucuronic acid (1-b-3) N-acetyl-D-glucosamine), is present in the tissue matrix and body fluids of all vertebrates. It plays a fundamental role in the regulation of cell migration and differentiation.
The majority of hyaluronon binding proteins belong to the cartilage link-proteins superfamily.
These can be divided into two groups, those that are true cellular adhesion molecules such as CD44 and those that are components of the extracellular matrix, such as cartilage-link protein itself.
Adhesion molecules in action
Endothelial and epithelial cells depend upon the contacts that they make with each other and with the extracellular matrix. Without this contact, the cells will die through a signaling cascade that induces apoptosis.
The two pathways above are necessary for survival and proliferation but the signaling pathway that actually induces apoptosis involves Jun-N-terminal Kinase (JNK). Normal activation of Jun is shown below.
But in the case of induction of apoptosis, caspase-3, which is activated by procaspase-8, cleaves MEKK-1 causing its activation and sensitization of the cell for apoptosis.
Attachment at focal adhesion sites is necessary to allow the formation of complexes necessary to signal entrance into an active cell cycle.
Concerted activation of Ras through growth factors and integrins triggers the ERK pathway and also stimulates a series of events that result in the activation of RhoA. RhoA plays a crucial role in regulating the inhibitor p21 which prevents protein kinase activation of cyclinD/CDK4 or cyclinE/CDK2 which regulate DNA synthesis.
Loss of adherent junctions induces de-differentiation.
The family of caspases contain a cysteine residue in the catalytic site and cleave their substrates at a consensus motif, Asp-Glu-Val-Asp (hence, CYsteine-ASpartate-paoteASES). There are two classes of caspases, those that cleave other caspases and those that cleave other non-caspase proteins. Activity of these enzymes is suppressed through binding to inhibitory proteins that prevent their dimerization.
Cellular targets of caspases are:
- inactivation or destruction of inhibitors of apoptosis
- inactivation of the inhibityory protein (ICAD) of the caspase activated DNAase (CAD).
- inactivation of Bcl-2, a protein that maintains caspases in their inactive state.
- destruction of cellular compartments and signal transduction pathways.
- degradation of proteins that direct the organization of the cytoskeleton: gelsolin, p21-activated protein kinase (PAK), FAK, lamin.
- destruction of the machinery that repairs and replicates DNA
- degradation of repair enzymes, DNA-dependent protein kinase (DNA-PK), the s;licing enzyme U1-70K and replication factor C.
The role of Bcl-2 in regulating caspases.
Caspases can also be activated through external signals.
Caspases can also be activated by injury to mitochondria resulting from drugs that induce the leakage of cytochrome C.
All of these inductive pathways result in activation of caspase 3.
Leukocyte Trafficking and adhesion molecules
NF - kB and the expression of adhesion molecules.
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