| insulin receptor substrate 4 | OKDB#: 1883 |
| Symbols: | IRS4 | Species: | human | ||
| Synonyms: | IRS-4, PY160 | Locus: | Xq22.3 in Homo sapiens |
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| General Comment | NCBI Summary: IRS4 encodes the insulin receptor substrate 4, a cytoplasmic protein that contains many potential tyrosine and serine/threonine phosphorylation sites. Tyrosine-phosphorylated IRS4 protein has been shown to associate with cytoplasmic signalling molecules that contain SH2 domains. The IRS4 protein is phosphorylated by the insulin receptor tyrosine kinase upon receptor stimulation.. [provided by RefSeq, Jul 2008] | ||||
| General function | |||||
| Comment | |||||
| Cellular localization | Cytoplasmic | ||||
| Comment | Selective alterations in insulin receptor substrates-1, -2 and -4 in theca but not granulosa cells from polycystic ovaries. Yen HW et al. (2004) The elevated insulin concentrations that occur in many women with polycystic ovary syndrome (PCOS) can contribute significantly to ovarian hyperandrogenism. The objective of the present study was to compare the content of proximal insulin signalling molecules in theca and granulosa cells between polycystic ovaries and regular cycling controls. Individual follicles (3-7 mm) were obtained from 11 women with PCOS and 10 regularly cycling control women. The theca and granulosa cells were microdissected from each follicle. Total protein was extracted and signalling proteins were measured by western blot analysis. There was no difference in insulin receptor content between PCOS and controls in either theca or granulosa cells. Insulin receptor substrate (IRS)-1 and -2 were increased (P<0.05), but IRS-4 was decreased (P<0.03) in PCOS theca cells. There were no changes in IRS-1, -2 or -4 in granulosa cells. IRS-3 was undetectable in all samples. There were no changes in phosphatidyl inositol-3 kinase catalytic subunits p110alpha or p110beta in either theca or granulosa cells. These data demonstrate cell-specific alterations in IRS protein concentrations in theca cells from polycystic ovaries that are consistent with an exaggerated amplification of the insulin signal and which may play an important role in ovarian hyperandrogenism and thecal hyperplasia.////////////////// | ||||
| Ovarian function | |||||
| Comment | |||||
| Expression regulated by | |||||
| Comment | |||||
| Ovarian localization | Granulosa, Theca | ||||
| Comment | P3-32] Insulin Receptor Substrate-4 Is Selectively Decreased in Theca Cells from Polycystic Ovaries. Hui-Wen Yen, Artur J Jakimiuk, Iqbal Munir, Denis A Magoffin Ob & Gyn, Cedars-Sinai Burns and Allen Res Inst, Los Angeles, CA; 2nd Clin of Surg Gyn, Univ Sch of Med, Lublin, Poland Polycystic ovary syndrome (PCOS), characterized by hyperandrogenism and chronic anovulation, is the most common reproductive disorder in premenopausal women. Approximately 50% of women with PCOS exhibit insulin resistance and mild hyperinsulinemia. A variety of in vitro and in vivo studies indicate that the elevated insulin contributes significantly to ovarian hyperandrogenism by binding and activating the insulin receptor. The intracellular actions of insulin are mediated by phosphorylation of the insulin receptor substrate (IRS) proteins IRS-1, IRS-2, IRS-3, and IRS-4. Although IRS-1 and -2 are major mediators of insulin action, recent data indicate that IRS-3 and -4 may suppress the functions of IRS-1 and -2. Previously we demonstrated a specific increase in both IRS-1 and -2 in PCOS theca cells in the absence of changes in insulin receptors. There are no data regarding IRS-3 and -4 in human theca cells. The objectives of this study were to compare IRS-1, -2, -3, and -4 in control and PCOS theca and granulosa cells and to determine if alterations in IRS concentrations were reflected in altered phosphatidylinositol-3 (PI-3) kinase concentrations. Individual follicles from 3 to 7 mm in diameter were obtained from 11 women with PCOS and 10 regularly cycling control women. The theca and granulosa cells were microdissected from each follicle. Total protein was extracted and signaling proteins were measured by Western blot analysis. Data were quantitated by fluorescence scanning and are expressed as the ratio of PCOS divided by control. IRS-3 was undetectable in all samples. As expected IRS-1 (1.54 0.13) and -2 (1.41 0.11) were increased (P<0.05), but IRS-4 (0.67 0.09) decreased (P<0.03) in PCOS theca cells. There were no changes in IRS-1 (0.98 0.27), -2 (1.41 0.11), or -4 (1.20 0.16) in granulosa cells. There were no changes in PI-3 kinase catalytic subunits p110 or p110 in either theca or granulosa cells. These data demonstrate that although there are not generalized alterations of the proximal components of the intracellular insulin signaling pathways, there are cell specific alterations in IRS protein concentrations in theca cells from polycystic ovaries. The increases in IRS-1 and -2 coupled with decreased IRS-4 are consistent with an exaggerated amplification of the insulin signal in PCOS theca cells that may play an important role in ovarian hyperandrogenism. | ||||
| Follicle stages | Antral | ||||
| Comment | |||||
| Phenotypes |
PCO (polycystic ovarian syndrome) |
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| Mutations | 0 mutations | ||||
| Genomic Region | show genomic region | ||||
| Phenotypes and GWAS | show phenotypes and GWAS | ||||
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| created: | June 25, 2003, 12:07 p.m. | by: |
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| last update: | Jan. 22, 2016, 1:11 p.m. | by: | hsueh email: |
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