The insulin receptor is encoded by a single copy gene located on chromosome 19 in the human. In addition, at least two other highly homologous genes have been identified. One gene encodes the type 1 insulin-like growth factor (IGF) receptor. The third gene in the family encodes an orphan receptor tyrosine kinase that has been named the insulin receptor-related receptor (IRR). We have cloned the cDNA molecules encoding human and mouse IRR. Generally, the predicted structure of IRR is similar to those of the receptors for insulin and IGF-1. However, the phosphotyrosine content of IRR is not increased by incubating the cells with insulin, IGF-1, or proinsulin. In an effort to identify a ligand for IRR, we used an assay based upon the ability to stimulate autophosphorylation of IRR, and have accomplished partial purification of a protein factor from rat brain that activates phosphorylation of IRR. However, indirect evidence suggests that this activator protein may not bind directly to IRR; therefore, the protein appears not to be a ligand, but rather activates tyrosine phosphorylation by an indirect mechanism.
