UBC Theses and Dissertations
A multifunctional protein : Phosphoglucose isomerase / autocrine motility factory / neuroleukin Y, Nathalie
Phosphoglucose isomerase (PGI) is a glycolytic enzyme that moonlights as a cellular cytokine. The protein is also known as autocrine motility factor (AMF), neuroleukin and maturation factor. PGI/AMF interaction with its receptor interaction is pH-dependent. Indeed, at neutral pH, PGI/AMF binds its receptor AMFR at the cell surface and can be endocytosed via two different pathways: caveolae/raft-dependent endocytosis to the smooth ER or clathrin-dependent endocytosis to multivesicular bodies (MVBs). Internalized PGI/AMF can recycle from MVBs to the plasma membrane where it can undergo further rounds of endocytosis and recycling. Recycling receptor-ligand complexes can also be sequestered via stable association with FN fibrils. Recent data show that, at acid pH, endocytosis is inhibited and PGI/AMF binds directly to FN fibrils or to HS. Heparan sulfate proteoglycans, when expressed on the surface of cells, modulate the actions of a large number of extracellular ligands while fibronectin is involved in many cellular processes such as tissue repair and cell migration/adhesion. However, the mechanisms that regulate PGI/AMF binding to its receptors still remain unclear. PGI/AMF cytokine activity, associated with several diseases, has been reported in rheumatoid synovial fluid and its deposition on synovial surfaces and ability to induce an autoimmune response in rheumatoid arthritis (RA) identified it as a possible autoantigen different from normal circulating PGI/AMF. However, more recent manuscripts have questioned the prevalence of an autoimmune response to PGI in RA . In this study, recombinant PGI constructs were used to characterize PGI interactions and functions. We demonstrate that PGI behaves differently after N or C-terminal residue additions. Our data also suggest that monomerization but not enzymatic activity is necessary to induce cell motility at neutral pH. The putative function of PGI in RA was assessed and using the recombinant PGI constructs and PGI autoantibodies was found to be species and conformation-dependant.
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