The long-term objective of this proposal is to obtain a better understanding of the molecular mechanisms governing the first step in tumor cell dissemination, namely motility. To accomplish this we propose to define the structural-functional relationship and mechanism of action of an autocrine motility factor (AMF) and its receptor (AMFR). We found AMF to be a phosphoglucose isomerase (PGI); a glycolytic enzyme that functions as an extracellular cytokine (AMF/neuroleukin/maturation factor). The AMFR is a unique member of the seven-transmembrane domain G-protein-coupled receptors (CXC2CR-1), AMF/PGI contains the CXXC thioredoxin-box motif which resembles the CC and CXC motifs of chemokines. AMF/PGI signaling pathway is similar to that of the chemokines and involves cytoskeletal rearrangement and morphological alteration mediated by small RhoA-like GTPases. We show here (Progress Report) that AMF/PGI is a hypoxic inducible gene, which in turn upregulates the expression of vascular endothelial growth factor (VEGF) and its receptor in endothelial cells and affects cellular oncogenic phenotype. Thus, we hypothesize that there is a cross-talk among hypoxia, glycolysis and angiogenesis and that AMF/PGI is a key molecule regulating, in part, tumor growth, angiogenesis, cell motility, invasion and metastasis. In addition, we have crystallized the human AMF/PGI and have provided the first structural evidence to the dichotomy between the isomerase and the cytokine activities of the molecule and provides evidence that its secretion is regulated by post-translation modification Based on the above and the data outlined in the Progress Report we set the following Specific Aims for this renewal application: 1) To establish the structural-functional relationship of AMF/PGI activity, 2) To study the regulation of AMF/PGI expression under hypoxia and 3) To determine the role of AMFIPGI in angiogenesis. It is expected that the accomplishment of these aims will help in understanding how and which of its structural motif(s) regulates its cytokine activity, how the signaling loop of AMF/PGI is transduced via AMFR, and to unveil its molecular role during hypoxia and angiogenesis. It is expected that the information obtained from this proposal will be utilized for therapeutic interventions to slow or eliminate invasion of cancer cells.
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