MECHANISM OF ALTERNATIVE SPLICING OF HUMAN INSULIN RECEPTOR

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Insulin is essential for growth and development in addition to fuel metabolism. There are two variants of the insulin receptor (IR), which differ in the presence of 12-amino acids in the hormone-binding domain. The INSR gene is located on chromosome 19 and composed of 22 exons. The two IR protein variants arise from alternative splicing of exon 11. The IR lacking exon 11 (IR-A) is widely expressed and binds both insulin and IGF-II; the IR containing exon 11 (IR-B) has a more limited distribution, being expressed predominantly in the insulin - sensitive tissues (liver, muscle, adipocytes and kidney) and only binds insulin. The unique tissue distributions of the insulin receptor isoforms has lead to the suggestion that IR-B is the metabolic receptor and IR-A is a developmental receptor, but very little has been done to define their divergent physiological functions. Many lower organisms have insulin receptor gene homologues that control growth and longevity, not metabolism. It is thought that during evolution, insulin receptor function was hijacked to control glucose levels. The acquisition of this secondary function coincides with the appearance of exon 11. In organisms that contain exon 11, such as humans, monkeys, and rodents, insulin regulates glucose homeostasis, but in organisms that lack exon 11, such as Drosophila, C. elegans, Fugu (pufferfish), Aedes aegypti (mosquito) and Lymnaea stagnalis (pond snail), insulin does not. The insulin receptors original function to control growth has not been completely subjugated by its metabolic role in mammals, however, as humans with insulin receptor deletions also exhibit leprechaunism and stunted embryonic growth. The embryonic form of the insulin receptor lacks exon 11 and switches to include exon 11 in the neonatal period. These windows of expression suggest that the different receptor isoforms have specific functions. More importantly, a number of disease states, such as type II diabetes, aging, myotonic dystrophy and cancer, have decreased inclusion of exon 11. This makes the IR gene a particularly interesting model system for studies of RNA splicing. Our goal in this project is to understand how the expression of these two isoforms is regulated at the posttranscriptional level and to determine the physiological roles of the two receptor isoforms.