In 1989, Shier and Watt identified a gene whose sequence predicted that it encodes a new receptor that is in the family of insulin and insulin-like growth factor I receptors. Hence, it was given the name insulin receptor-related receptor (or IRR). However, the tissues that express this receptor, the ligand which binds to it and the physiological function of this receptor are unknown. The goal of the present grant is to learn more about this novel receptor. In preliminary studies we have identified the mRNA for this receptor in rat and human kidney (both adult and fetal) and in dog gastric parietal cells. One of the objectives of the proposed studies will be to further define the specific cells expressing this receptor. To this end, specific monoclonal and polyclonal antibodies will be generated. These antibodies and cDNA probes will be used to test for the presence of the receptor protein and mRNA, respectively, in both isolated primary kidney cells and cell lines. In addition, if some of the antibodies are found to be agonists, they will be used to explore the function of this receptor. A chimera composed of portions of the extracellular domain of the insulin receptor-related receptor on the backbone of the insulin receptor has also been constructed. This chimera did not bind insulin, insulin-like growth factor I or II, or relaxin, suggesting that IRR is not a receptor for these ligands. This and other chimeras will therefore be used to screen for the presence of a ligand for the insulin receptor-related receptor by looking for samples that stimulate the intrinsic kinase activity of the chimera. In addition, we will overproduce large amounts of the extracellular domain of IRR for use in purifying the ligand for IRR. Identification of the ligand for IRR as well as the tissue distribution of this receptor should aid in the determination of the physiological function of this molecule. From its location in the kidney and stomach parietal cells, this receptor could have a role in the regulation of blood pressure, acid production, etc. In addition, since this receptor has an intrinsic tyrosine kinase activity, it is possible that it is involved in growth control and may be involved in cancerous lesions of stomach and kidney.
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