THE IRS-2 GENE ON MURINE CHROMOSOME-8 ENCODES A UNIQUE SIGNALING ADAPTER FOR INSULIN AND CYTOKINE ACTION

Signal transduction by insulin and IGF-1, several interleukins (IL-2, IL-4, IL-9, IL-13), interferons, GH, and other cytokines involves IRS proteins, which link the receptors for these factors to signaling mole cules with Src homology-2 domains (SH2-proteins). We recently reported the amino acid sequence of murine IRS-2; in order to examine a potent ial genetic role for this molecule in disease, we isolated the murine IRS-2 gene and compared the expression pattern of IRS-2 against IRS-1. Like IRS-1, IRS-2 is encoded by a single exon. Whereas IRS-1 is locat ed on murine chomosome 1, IRS-2 is located on murine chromosome 8 near the insulin receptor. IRS-2 is expressed together with IRS-1 in many cells and tissues; however, IRS-2 predominates in murine hematopoietic cells where it may be essential for cytokine signaling; IRS-1 predomi nates in adipocytes and differentiated 3T3-L1 cells where it contribut es to the normal insulin response. In 32D cells, IRS-1 and IRS-2 under go differential tyrosine phosphorylation during insulin or IL-4 stimul ation, as assessed indirectly by interaction with various recombinant SH2 domains. Thus, signaling specificity through the IRS proteins may be accomplished by specific expression patterns and distinct phosphory lation patterns during interaction with various activated receptors.