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Title: An investigation into the function of two S100 proteins, S100A12 and MRP-14
Author: Robinson, Matthew James
ISNI:       0000 0001 3529 1555
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 2000
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MRP-8 and MRP-14 (S100A8 and S100A9) are homologous members of the S100 family of small acidic calcium binding proteins. These proteins are highly expressed as a complex by neutrophils, comprising 45% of the total cytosolic protein. Monocytes and certain squamous epithelia also express MRP-8 and MRP- 14. Another closely related S100 protein, S100A12, is expressed by neutrophils. S100A12 was cloned, and the recombinant protein expressed and purified. Immunohistochemistry showed S100A12 expression by squamous epithelia was similar to but more restricted than MRP-14 expression. S100A12 and MRP-14 failed to co-immunoprecipitate from neutrophil lysate, indicating that S100A12 does not exist in the complex with the MRP proteins. Previous work in our laboratory showed that recombinant MRP-14 (rMRP-14) activated the leukocyte integrin Mac-1 (CD11b/CD18) on neutrophils (Newton and Hogg, 1998). Further work demonstrated that rMRP-14 induced Mac-1 expression on T lymphoblasts and stimulated binding to the Mac-1 ligand fibrinogen (Newton, 1997). However, detailed analysis of the rMRP-14 induced adhesion of T lymphocytes and neutrophils to fibrinogen proved it was not mediated by Mac-1. The cell adhesion was dependent on rMRP-14 binding to fibrinogen and other Mac-1 ligands, such as denatured BSA. The rMRP-14 induced expression of Mac-1 on T lymphoblasts has also proved to be an artefact rMRP-14 bound heparin with high affinity. This interaction with heparin was different in nature to the binding to fibrinogen, and was probably maintained by ionic bonds formed with the sulphate substitutions. The binding site for heparin was discrete and distinct from the proteinaceous ligand-binding site. Further, rMRP-14 bound to the cell surface of T lymphoblasts and the microvascular endothelial cell line, HMEC-1. Initial studies indicate that the rMRP-14 bound to cell surface proteoglycans. It is proposed that the adhesion of neutrophils and T lymphoblasts is mediated by rMRP-14 binding both the immobilised ligand and the cell surfaces, thus acting as a "molecular glue".
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available