| insulin receptor substrate 1 | OKDB#: 1030 |
| Symbols: | IRS1 | Species: | human | ||
| Synonyms: | HIRS-1 | Locus: | 2q36.3 in Homo sapiens |
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| General Comment |
IRS-1 is a 160- to 185-kD phosphotyrosyl protein that is a substrate of the insulin
receptor tyrosine kinase and a putative participant in insulin signaling. This protein is found in a variety of insulin responsive cells and tissues. It exhibits no intrinsic enzyme
activity but is believed to serve as a docking protein involved in binding and activating other signal transduction
molecules after being phosphorylated on tyrosine by the insulin receptor kinase.
NCBI Summary: This gene encodes a protein which is phosphorylated by insulin receptor tyrosine kinase. Mutations in this gene are associated with type II diabetes and susceptibility to insulin resistance. [provided by RefSeq, Nov 2009] |
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| General function | Intracellular signaling cascade | ||||
| Comment | |||||
| Cellular localization | Cytoplasmic | ||||
| Comment | candidate123 | ||||
| Ovarian function | Follicle development, Antral follicle growth, Luteinization | ||||
| Comment | Insulin Receptor Substrate 1: The Hub Linking Follicle-stimulating Hormone to Phosphatidylinositol-3 Kinase Activation. Law NC et al. (2015) The ubiquitous phosphatidylinositol-3 kinase (PI3K) signaling pathway regulates many cellular functions. However, the mechanism by which G protein-coupled receptors (GPCRs) signal to activate PI3K is poorly understood. We have used ovarian granulosa cells (GCs) as a model to investigate this pathway, based on evidence that the GPCR agonist follicle-stimulating hormone (FSH) promotes the protein kinase A (PKA)- dependent phosphorylation of insulin receptor substrate 1 (IRS1) on tyrosine residues that activate PI3K. We report that in the absence of FSH, GCs secrete a subthreshold concentration of insulin-like growth factor-1 (IGF-1) that primes the IGF-1 receptor (IGF-1R) but fails to promote tyrosine phosphorylation of IRS1. FSH via PKA acts to sensitize IRS1 to the tyrosine kinase activity of the IGF-1R by activating protein phosphatase 1 (PP1) to promote dephosphorylation of inhibitory Ser/Thr residues on IRS1, including Ser789. Knockdown of PP1β blocks the ability of FSH to activate PI3K in the presence of endogenous IGF-1. Activation of PI3K thus requires both PKA-mediated relief of IRS1 inhibition and IGF-1R-dependent tyrosine phosphorylation of IRS1. Treatment with FSH and increasing concentrations of exogenous IGF-1 triggers synergistic IRS1 tyrosine phosphorylation at PI3K-activating residues that persists downstream through AKT and forkhead box O1 (FOXO1) to drive synergistic expression of genes that underlies follicle maturation. Based on the ability of GPCR agonists to synergize with IGFs to enhance gene expression in other cell types, PP1 activation to relieve IRS1 inhibition may be a more general mechanism by which GPCRs act with the IGF-1R to activate PI3K/AKT.////////////////// Prostaglandin F2{alpha} Represses IGF-I-Stimulated IRS1/Phosphatidylinositol-3-Kinase/AKT Signaling in the Corpus Luteum: Role of ERK and P70 Ribosomal S6 Kinase. Arvisais E et al. Little is known about the early intracellular events that contribute to corpus luteum regression. Experiments were designed to determine the effects of prostaglandin F2alpha (PGF2alpha) on phosphatidylinositol-3-kinase (PI3K)/Akt signaling in the corpus luteum in vivo and in vitro. Treatment of midluteal-phase cows with a luteolytic dose of PGF2alpha resulted in a rapid increase in ERK and mammalian target of rapamycin (mTOR)/p70 ribosomal protein S6 kinase (p70S6K1) signaling and a rapid suppression of Akt phosphorylation in luteal tissue. In vitro treatment of primary cultures of luteal cells with PGF2alpha also resulted in an increase in ERK and mTOR/p70S6K1 signaling and a diminished capacity of IGF-I to stimulate PI3K, Akt, and protein kinase C zeta activation. Accounting for the reductions in PI3K and Akt activation observed in response to PGF2alpha treatment, we found that PGF2alpha promoted the phosphorylation of serine residues (307, 612, 636) in the insulin receptor substrate 1 (IRS1) peptide sequence in vivo and in vitro. Serine phosphorylation of IRS1 was associated with reduced formation of IGF-I-stimulated IRS1/PI3Kp85 complexes. Furthermore, treatment with inhibitors of the MAPK kinase 1/ERK or mTOR/p70S6K1 signaling pathways prevented PGF2alpha-induced serine phosphorylation of IRS1 and abrogated the inhibitory actions of PGF2alpha on Akt activation. Taken together, these experiments provide compelling evidence that PGF2alpha treatment stimulates IRS1 serine phosphorylation, which may contribute to a diminished capacity to respond to IGF-I. It seems likely that the rapid changes in phosphorylation events are among the early events that mediate PGF2alpha-induced corpus luteum regression. | ||||
| Expression regulated by | FSH, LH, Growth Factors/ cytokines, mir145 | ||||
| Comment | PMID: 27799458 MicroRNA-145 Negatively Regulates Cell Proliferation Through Targeting IRS1 in Isolated Ovarian Granulosa Cells From Patients With Polycystic Ovary Syndrome. Carvalho CR, et al reported a novel signal transduction pathway for luteinizing hormone and its interaction with insulin and the activation of Janus kinase/signal transducer and activator of transcription and phosphoinositol 3-kinase/Akt pathways. The actions of LH are mediated through a single class of cell surface LH/human chorionic gonadotropin receptor, which is a member of the G protein-coupled receptor family. In the present study the authors showed that LH induced rapid tyrosine phosphorylation and activation of the Janus kinase 2 (JAK2) in rat ovary. Upon JAK2 activation, tyrosine phosphorylation of signal transducer and activator of transcription-1 (STAT-1), STAT-5b, insulin receptor substrate-1 (IRS-1), and Src homology and collagen homology (Shc) were detected. In addition, LH induced IRS-1/phosphoinositol 3-kinase and Shc /growth factor receptor-binding protein 2 (Grb2) associations and downstream AKT (protein kinase B, homologous to v-AKT) serine phosphorylation and ERK tyrosine phosphorylation, respectively. The simultaneous infusion of insulin and LH induced higher phosphorylation levels of JAK2, STAT5b, IRS-1, and AKT compared with each hormone alone in the whole ovary of normal rats. By immunohistochemistry the authors demonstrated that these late events take place in follicular cells and both external and internal theca. These results indicate a new signal transduction pathway for LH and show that there is positive cross-talk between the insulin and LH signaling pathways at the level of phosphoinositol 3-kinase/AKT pathway in this tissue. Dihydrotestosterone Inhibits Insulin-Stimulated Cyclin D2 mRNA Expression in Rat Ovarian Granulosa Cells by Reducing the Phosphorylation of Insulin Receptor Substrate -1 Kayampilly PP, et al . The effect of 5 alpha dihydrotestosterone (DHT) on insulin-stimulated granulosa cell proliferation was examined using cyclin D2 mRNA as a marker. Granulosa cells from 3 day estradiol-treated immature rats showed a concentration dependent increase in cyclin D2 mRNA expression in response to insulin. Exposure to DHT reduced the insulin-stimulated cyclin D2 mRNA expression. Inhibition of the two insulin-signaling pathways, ERK and PI 3 kinase, by using specific inhibitors, also reduced this insulin-stimulated response. These results suggest that both ERK and PI 3 kinase signaling are involved in insulin stimulated granulosa cell proliferation. DHT exposure resulted in reduced insulin-stimulated ERK phosphorylation. DHT treatment also reduced the insulin mediated IRS-1 and Raf-1 phosphorylation, the upstream molecules of ERK in insulin signaling pathway. Additionally, inhibition of insulin stimulated PI 3 kinase activation reduced ERK phosphorylation. The present study therefore shows that the inhibitory effect of DHT on insulin stimulated granulosa cell proliferation occurs early in the signaling pathway at the level of IRS-1 phosphorylation, leading to reduced ERK phosphorylation and subsequent inhibition of cyclin D2 mRNA expression. | ||||
| Ovarian localization | Granulosa | ||||
| Comment | The effect of short-term nutritional supplementation of ewes with lupin grain (Lupinus luteus) on folliculogenesis, the concentrations of hormones and glucose in plasma and follicular fluid and the follicular levels of P450 aromatase and IRS-1, 2 and 4. Somchit-Assavacheep A et al. An experiment was conducted on 48 ewes during follicular and luteal phases of the oestrous cycle to determine the effect of a 5-day lupin grain supplementation (500g/day) on folliculogenesis, plasma concentrations of glucose, insulin, follicle stimulating hormone (FSH) and oestradiol-17, follicular fluid concentrations of glucose, oestradiol-17, androstenedione and progesterone and the levels of P450aromatase and IRS-1, IRS-2 and IRS-4 in theca and granulosa cells. Average weight did not differ between lupin-fed and control groups. The numbers of follicles were increased (P<0.05) in the lupin-fed group. The plasma concentrations of glucose (P<0.05) and insulin (P<0.001) were higher in lupin-fed ewes. The plasma concentrations of FSH were not different but those of oestradiol-17 were decreased (P<0.001) in the lupin-fed group. The follicular fluid concentration of oestradiol-17 (P<0.05) and the level of P450aromatase in granulosa cells (P<0.05) were both decreased in the lupin-fed group, but only during the follicular phase. The level of P450aromatase in granulosa cells was positively correlated with the concentration of oestradiol-17 in follicular fluid (r=0.820; P<0.001). The levels of IRS-1 and IRS-2 in theca and granulosa cell lysates were increased in the lupin-fed group. These data suggest that insulin has a local role in the control of folliculogenesis and is likely to be a mediator of the effects of dietary energy intake on ovulation rate. We suggest that insulin acting through IRS proteins mediates the reproductive actions of insulin in the follicle and that IRS-1 and IRS-2 are nutritionally regulated mediators of the action of insulin in the follicle. Wu XK et al 2000 evaluated the role of insulin-receptor substrate (IRS)-1 and -2 in ovary dysfunction in women with insulin resistance. Sections of ovary were obtained at the time of cesarean section from five volunteers without medical complications and three patients with gestational diabetes mellitus. Immunoblotting with specific monoclonal and polyclonal antibodies showed the presence of 165-kDa and 183-kDa proteins that corresponded to the size of IRS-1 and IRS-2, respectively, in normal pregnant ovaries and human cultured follicles. Immunohistochemical staining showed that positive IRS-2 expression in antral follicles was restricted to theca internal cells in ovulatory ovaries but was distributed widely in all compartments of follicles in different stages in polycystic ovaries. Compared with follicles at a similar stage of development in ovulatory ovaries, follicles in polycystic ovaries showed decreased staining for IRS-1 in granulosa cells but increased staining for IRS-2 in theca internal cells. This study highlights a shift of the follicular insulin signal protein from IRS-1 to IRS-2 in insulin-resistant states and suggests an association between this change and ovarian abnormality in PCOS and gestational diabetes mellitus. | ||||
| Follicle stages | Antral | ||||
| Comment | |||||
| Phenotypes |
PCO (polycystic ovarian syndrome) |
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| Mutations |
6 mutations
Species: mouse
Species: human
Species: human
Species: human
Species: human
Species: human
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| Genomic Region | show genomic region | ||||
| Phenotypes and GWAS | show phenotypes and GWAS | ||||
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| created: | Oct. 3, 2000, midnight | by: |
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| last update: | March 22, 2020, 4:21 a.m. | by: | hsueh email: |
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