Protein of the Month |
March 2006
MORE ON THIS MONTH’S PROTEIN
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OTHER PROTEINS OF INTEREST |
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Molecule of the Month: Tissue Factor |
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Tissue Factor
By Jennifer McDowall
Blood provides a means of circulating various cells and molecules around the body to meet its varied requirements: red blood cells distribute oxygen to tissues and remove waste carbon dioxide, white blood cells seek out and destroy invading organisms, and a whole host of different molecules are transported, ranging from nutrients to messenger molecules such as hormones that carry signals to various tissues to direct and control their function.
The circulatory system is closed, such that molecules can diffuse through vessel walls, but under normal circumstances, blood remains within the confines of the system. A closed system enables a considerable amount of pressure to be built up within it, which in turn allows the action of the heart and muscles to pump the blood around quickly and efficiently throughout the body. Blood pressure is measured as the force of blood against the arterial walls, and is recorded as the systolic pressure (during heart beats) over the diastolic pressure (between heart beats as heart relaxes), where normal blood pressure is less than 120/80. However, there is a downside to such a pressured system: any damage to the system could result in rapid blood loss if it is not repaired promptly.
Blood clotting, or coagulation, is a rapid response to tissue damage. Its speed comes from a cascade system of activation, whereby a series on enzymes work in rapid succession to amplify a small response into a large one. In this way, only a few molecules need to be activated initially to trigger a substantial response at the site of damage.
Tissue
Factor, Starting the Coagulation Cascade
Tissue Factor (also known as thromboplastin) is the principal initiator of the coagulation cascade. It is a 47-kDa transmembrane glycoprotein receptor found on the surface of a variety of cells, including platelets, leukocytes, fibroblasts, and endothelial cells, as well as in the smooth muscle cells surrounding the vessel walls; however, it is not expressed in blood cells or in the cells that line the blood vessels. Tissue Factor is expressed in response to injury, as well as to a number of different extracellular stimuli, including LPS, TFN-a, IL-1, IL-2, IL-6, interferon-g, lipoprotein, FIIa, plasmin, angiotensin II, and hypoxia.
Tissue Factor shares a large degree of homology with the interferon class of receptors, both of which are members of the type II cytokine receptor superfamily. Its extracellular region, which contains the FVII/FVIIa binding site, comprises over 80% of the molecule and has an immunoglobulin-like beta-sandwich fold, while the small intracellular C-terminal tail appears to contain two phosphorylation sites for intracellular signalling.
Tissue Factor plays many diverse roles, and in addition to promoting blood coagulation, it is involved in inflammation, embryonic development, angiogenesis, tumour metastasis, cell adhesion/migration, and innate immunity. Tissue Factor participates in cell signalling via two distinct mechanisms: (1) proteolysis-independent signalling through the cytoplasmic domain of Tissue Factor (possibly involving filamin 1, which provides an intracellular link to transmit the signal), and (2) proteolysis-dependent signalling through the activation of factor VII, which in turn activates protease-activated receptors that can impact multiple pathways.
Next: The
Blood Coagulation Cascade