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Morris F White - One of the best experts on this subject based on the ideXlab platform.
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IRS proteins and diabetic complications
Diabetologia, 2016Co-Authors: Deborah P. Lavin, Morris F White, Derek P BrazilAbstract:IRS proteins are cellular adaptor molecules that mediate many of the key metabolic actions of insulin. When tyrosine is phosphorylated by the activated insulin receptor, IRS proteins recruit downstream effectors, such as phosphoinositide 3-kinase and mitogen-activated protein kinase, in order to elicit cellular responses such as glucose uptake, lipid metabolism and cell proliferation. There are two main IRS proteins in humans (IRS1 and IRS2), both of which are widely expressed. Given their central role in the insulin signalling pathway, it is not surprising that male mice lacking Irs1 or Irs2 present with elevated blood glucose or type 2 diabetes, respectively. For reasons yet to be identified, female Irs2 ^−/− mice do not develop type 2 diabetes. A number of organs are affected by complications of diabetes; macrovascular complications include stroke and coronary artery disease, while nephropathy, neuropathy and retinopathy fall into the category of microvascular complications. Given the serious consequences of these complications on patient morbidity and mortality, it is essential to identify the molecular pathogenesis underlying diabetic complications, with a view to improving therapeutic intervention and patient outcomes. A number of recently published papers have converged on the hypothesis that the loss of insulin signalling and IRS proteins is instrumental to the development and/or progression of diabetic complications. This review will summarise some highlights from the published work in which this hypothesis is discussed.
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insulin and metabolic stress stimulate multisite serine threonine phosphorylation of insulin receptor substrate 1 and inhibit tyrosine phosphorylation
Journal of Biological Chemistry, 2014Co-Authors: Nancy J Hancer, Wei Qiu, Christine E Cherella, Kyle D Copps, Morris F WhiteAbstract:IRS1 and IRS2 are key substrates of the insulin receptor tyrosine kinase. Mass spectrometry reveals more than 50 phosphorylated IRS1 serine and threonine residues (Ser(P)/Thr(P) residues) in IRS1 from insulin-stimulated cells or human tissues. We investigated a subset of IRS1 Ser(P)/Thr(P) residues using a newly developed panel of 25 phospho-specific monoclonal antibodies (αpS/TmAbIrs1). CHO cells overexpressing the human insulin receptor and rat IRS1 were stimulated with insulin in the absence or presence of inhibitors of the PI3K → Akt → mechanistic target of rapamycin (mTOR) → S6 kinase or MEK pathways. Nearly all IRS1 Ser(P)/Thr(P) residues were stimulated by insulin and significantly suppressed by PI3K inhibition; fewer were suppressed by Akt or mTOR inhibition, and none were suppressed by MEK inhibition. Insulin-stimulated Irs1 tyrosine phosphorylation (Tyr(P)Irs1) was enhanced by inhibition of the PI3K → Akt → mTOR pathway and correlated with decreased Ser(P)-302Irs1, Ser(P)-307Irs1, Ser(P)-318Irs1, Ser(P)-325Irs1, and Ser(P)-346Irs1. Metabolic stress modeled by anisomycin, thapsigargin, or tunicamycin increased many of the same Ser(P)/Thr(P) residues as insulin, some of which (Ser(P)-302Irs1, Ser(P)-307Irs1, and four others) correlated significantly with impaired insulin-stimulated Tyr(P)Irs1. Thus, IRS1 Ser(P)/Thr(P) is an integrated response to insulin stimulation and metabolic stress, which associates with reduced Tyr(P)Irs1 in CHOIR/IRS1 cells.
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Irs2 and IRS4 synergize in non-LepRb neurons to control energy balance and glucose homeostasis.
Molecular metabolism, 2013Co-Authors: Marianna Sadagurski, X. Charlie Dong, Martin G. Myers, Morris F WhiteAbstract:Insulin receptor substrates (Irs1, 2, 3 and IRS4) mediate the actions of insulin/IGF1 signaling. They have similar structure, but distinctly regulate development, growth, and metabolic homeostasis. Irs2 contributes to central metabolic sensing, partially by acting in leptin receptor (LepRb)-expressing neurons. Although IRS4 is largely restricted to the hypothalamus, its contribution to metabolic regulation is unclear because IRS4-null mice barely distinguishable from controls. We postulated that Irs2 and IRS4 synergize and complement each other in the brain. To examine this possibility, we investigated the metabolism of whole body IRS4(-/y) mice that lacked Irs2 in the CNS (bIrs2(-/-)·IRS4(-/y)) or only in LepRb-neurons (Lepr (∆Irs2) ·IRS4 (-/y) ). bIrs2(-/-)·IRS4(-/y) mice developed severe obesity and decreased energy expenditure, along with hyperglycemia and insulin resistance. Unexpectedly, the body weight and fed blood glucose levels of Lepr (∆Irs2) ·IRS4 (-/y) mice were not different from Lepr (∆Irs2) mice, suggesting that the functions of Irs2 and IRS4 converge upon neurons that are distinct from those expressing LepRb.
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regulation of insulin sensitivity by serine threonine phosphorylation of insulin receptor substrate proteins irs1 and irs2
Diabetologia, 2012Co-Authors: Kyle D Copps, Morris F WhiteAbstract:The insulin receptor substrate proteins IRS1 and IRS2 are key targets of the insulin receptor tyrosine kinase and are required for hormonal control of metabolism. Tissues from insulin-resistant and diabetic humans exhibit defects in IRS-dependent signalling, implicating their dysregulation in the initiation and progression of metabolic disease. However, IRS1 and IRS2 are regulated through a complex mechanism involving phosphorylation of >50 serine/threonine residues (S/T) within their long, unstructured tail regions. In cultured cells, insulin-stimulated kinases (including atypical PKC, AKT, SIK2, mTOR, S6K1, ERK1/2 and ROCK1) mediate feedback (autologous) S/T phosphorylation of IRS, with both positive and negative effects on insulin sensitivity. Additionally, insulin-independent (heterologous) kinases can phosphorylate IRS1/2 under basal conditions (AMPK, GSK3) or in response to sympathetic activation and lipid/inflammatory mediators, which are present at elevated levels in metabolic disease (GRK2, novel and conventional PKCs, JNK, IKKβ, mPLK). An emerging view is that the positive/negative regulation of IRS by autologous pathways is subverted/co-opted in disease by increased basal and other temporally inappropriate S/T phosphorylation. Compensatory hyperinsulinaemia may contribute strongly to this dysregulation. Here, we examine the links between altered patterns of IRS S/T phosphorylation and the emergence of insulin resistance and diabetes.
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c jun n terminal kinase jnk mediates feedback inhibition of the insulin signaling cascade
Journal of Biological Chemistry, 2003Co-Authors: Yong Hee Lee, Jodel Giraud, Roger J Davis, Morris F WhiteAbstract:Activation of the c-Jun N-terminal kinase (JNK) by proinflammatory cytokines inhibits insulin signaling, at least in part, by stimulating phosphorylation of rat/mouse insulin receptor substrate 1 (Irs1) at Ser307(Ser312 in human IRS1). Here we show that JNK mediated feedback inhibition of the insulin signal in mouse embryo fibroblasts, 3T3-L1 adipocytes, and 32DIR cells. Insulin stimulation of JNK activity required phosphatidylinositol 3-kinase and Grb2 signaling. Moreover, activation of JNK by insulin was inhibited by a cell-permeable peptide that disrupted the interaction of JNK with cellular proteins. However, the direct binding of JNK to Irs1 was not required for its activation by insulin, whereas direct binding was required for Ser307 phosphorylation of Irs1. Insulin-stimulated Ser307 phosphorylation was reduced 80% in cells lacking JNK1 and JNK2 or in cells expressing a mutant Irs1 protein lacking the JNK binding site. Reduced Ser307phosphorylation was directly related to increased insulin-stimulated tyrosine phosphorylation, Akt phosphorylation, and glucose uptake. These results support the hypothesis that JNK is a negative feedback regulator of insulin action by phosphorylating Ser307 in Irs1.
Tiebang Kang - One of the best experts on this subject based on the ideXlab platform.
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Phosphorylation of IRS4 by CK1γ2 promotes its degradation by CHIP through the ubiquitin/lysosome pathway.
Theranostics, 2018Co-Authors: Li Zhong, Zhuo Wang, Huiming Chen, Dan Liao, Ruhua Zhang, Hongyu Zhang, Tiebang KangAbstract:IRS4, a member of the insulin receptor substrate protein family, can induce constitutive PI3K/AKT hyperactivation and cell proliferation even in the absence of insulin or growth factors and promote tumorigenesis, but its regulation has only been explored at the transcriptional level. Methods: Scansite was used to predict the potential protein kinases that may regulate the functions of IRS4, and mass spectrometry was used to identify the E3 ligase for IRS4. The protein interaction was carried out by immunoprecipitation, and protein stability was measured by cycloheximide treatment. In vitro kinase assay was used to determine the phosphorylation of IRS4 by casein kinase 1γ2 (CK1γ2). Colony formation assay and xenograft-bearing mice were employed to assess the cancer cell growth in vitro and in vivo, respectively. Immunohistochemistry was performed to examine protein levels of both IRS4 and CK1γ2 in osteosarcoma specimens and their relationship was evaluated by χ2 test. Two-tailed Student's t-test or the Mann-Whitney U test were used to compare the differences between subgroups. Results: IRS4 was phosphorylated at Ser859 by CK1γ2 in vitro and in vivo, which promoted the polyubiquitination and degradation of IRS4 through the ubiquitin/lysosome pathway by the carboxyl terminus of Hsc70-interacting protein(CHIP). Using osteosarcoma cell lines, the ectopic nonphosphorylated mutant of IRS4 by CK1γ2 triggered higher level of p-Akt and displayed faster cell proliferation and cancer growth in vitro and in nude mice. In addition, a negative correlation in protein levels between CK1γ2 and IRS4 was observed in osteosarcoma cell lines and tissue samples. Conclusions: IRS4, as a new substrate of CHIP, is negatively regulated by CK1γ2 at the posttranslational level, and specific CK1γ2 agonists may be a potentially effective strategy for treating patients with osteosarcoma.
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phosphorylation of IRS4 by ck1γ2 promotes its degradation by chip through the ubiquitin lysosome pathway
Theranostics, 2018Co-Authors: Li Zhong, Zhuo Wang, Huiming Chen, Dan Liao, Ruhua Zhang, Hongyu Zhang, Tiebang KangAbstract:IRS4, a member of the insulin receptor substrate protein family, can induce constitutive PI3K/AKT hyperactivation and cell proliferation even in the absence of insulin or growth factors and promote tumorigenesis, but its regulation has only been explored at the transcriptional level. Methods: Scansite was used to predict the potential protein kinases that may regulate the functions of IRS4, and mass spectrometry was used to identify the E3 ligase for IRS4. The protein interaction was carried out by immunoprecipitation, and protein stability was measured by cycloheximide treatment. In vitro kinase assay was used to determine the phosphorylation of IRS4 by casein kinase 1γ2 (CK1γ2). Colony formation assay and xenograft-bearing mice were employed to assess the cancer cell growth in vitro and in vivo, respectively. Immunohistochemistry was performed to examine protein levels of both IRS4 and CK1γ2 in osteosarcoma specimens and their relationship was evaluated by χ2 test. Two-tailed Student's t-test or the Mann-Whitney U test were used to compare the differences between subgroups. Results: IRS4 was phosphorylated at Ser859 by CK1γ2 in vitro and in vivo, which promoted the polyubiquitination and degradation of IRS4 through the ubiquitin/lysosome pathway by the carboxyl terminus of Hsc70-interacting protein(CHIP). Using osteosarcoma cell lines, the ectopic nonphosphorylated mutant of IRS4 by CK1γ2 triggered higher level of p-Akt and displayed faster cell proliferation and cancer growth in vitro and in nude mice. In addition, a negative correlation in protein levels between CK1γ2 and IRS4 was observed in osteosarcoma cell lines and tissue samples. Conclusions: IRS4, as a new substrate of CHIP, is negatively regulated by CK1γ2 at the posttranslational level, and specific CK1γ2 agonists may be a potentially effective strategy for treating patients with osteosarcoma.
A Encinasgrandes - One of the best experts on this subject based on the ideXlab platform.
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spotted fever group rickettsiae in ticks feeding on humans in northwestern spain is rickettsia conorii vanishing
Annals of the New York Academy of Sciences, 2006Co-Authors: Pedro Fernandezsoto, Ricardo Perezsanchez, Rufino Alamosanz, A EncinasgrandesAbstract:: During a 7-year study, we identified and analyzed by PCR 4,049 ticks removed from 3,685 asymptomatic patients in Castilla y Leon (northwestern Spain). A total of 320 ticks (belonging to 10 species) were PCR-positive for rickettsiae. Comparison of amplicon sequences in databases enabled us to identify eight different spotted fever group (SFG) rickettsiae: Rickettsia slovaca, Rickettsia sp. IRS3/IRS4, R. massiliae/Bar29, R. aeschlimannii, Rickettsia sp. RpA4/DnS14, R. helvetica, Rickettsia sp. DmS1, and R. conorii. Although Mediterranean spotted fever (MSF) is an endemic disease in Castilla y Leon, R. conorii was found in only one Rhipicephalus sanguineus tick, whereas other pathogenic SFG rickettsiae were much more prevalent in the same area. Our data suggest that in Castilla y Leon, many MSF or MSF-like cases attributed to R. conorii could have been actually caused by other SFG rickettsiae present in ticks biting people in this region of Spain.
Raoul C M Hennekam - One of the best experts on this subject based on the ideXlab platform.
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mutations in IRS4 are associated with central hypothyroidism
Journal of Medical Genetics, 2018Co-Authors: Charlotte A Heinen, Emmely M De Vries, Marielle Alders, Hennie Bikker, Nitash Zwavelingsoonawala, Erica L T Van Den Akker, Boudewijn Bakker, Gera Hoorwegnijman, Ferdinand Roelfsema, Raoul C M HennekamAbstract:Background Four genetic causes of isolated congenital central hypothyroidism (CeH) have been identified, but many cases remain unexplained. We hypothesised the existence of other genetic causes of CeH with a Mendelian inheritance pattern. Methods We performed exome sequencing in two families with unexplained isolated CeH and subsequently Sanger sequenced unrelated idiopathic CeH cases. We performed clinical and biochemical characterisation of the probands and carriers identified by family screening. We investigated IRS4 mRNA expression in human hypothalamus and pituitary tissue, and measured serum thyroid hormones and Trh and Tshb mRNA expression in hypothalamus and pituitary tissue of IRS4 knockout mice. Results We found mutations in the insulin receptor substrate 4 (IRS4) gene in two pairs of brothers with CeH (one nonsense, one frameshift). Sequencing of IRS4 in 12 unrelated CeH cases negative for variants in known genes yielded three frameshift mutations (two novel) in three patients and one male sibling. All male carriers (n=8) had CeH with plasma free thyroxine concentrations below the reference interval. MRI of the hypothalamus and pituitary showed no structural abnormalities (n=12). 24-hour thyroid-stimulating hormone (TSH) secretion profiles in two adult male patients showed decreased basal, pulsatile and total TSH secretion. IRS4 mRNA was expressed in human hypothalamic nuclei, including the paraventricular nucleus, and in the pituitary gland. Female knockout mice showed decreased pituitary Tshb mRNA levels but had unchanged serum thyroid hormone concentrations. Conclusions Mutations in IRS4 are associated with isolated CeH in male carriers. As IRS4 is involved in leptin signalling, the phenotype may be related to disrupted leptin signalling.
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Mutations in IRS4 are associated with central hypothyroidism
Journal of medical genetics, 2018Co-Authors: Charlotte A Heinen, Emmely M De Vries, Marielle Alders, Hennie Bikker, Erica L T Van Den Akker, Boudewijn Bakker, Ferdinand Roelfsema, Nitash Zwaveling-soonawala, Gera Hoorweg-nijman, Raoul C M HennekamAbstract:Four genetic causes of isolated congenital central hypothyroidism (CeH) have been identified, but many cases remain unexplained. We hypothesised the existence of other genetic causes of CeH with a Mendelian inheritance pattern. We performed exome sequencing in two families with unexplained isolated CeH and subsequently Sanger sequenced unrelated idiopathic CeH cases. We performed clinical and biochemical characterisation of the probands and carriers identified by family screening. We investigated IRS4 mRNA expression in human hypothalamus and pituitary tissue, and measured serum thyroid hormones and Trh and Tshb mRNA expression in hypothalamus and pituitary tissue of IRS4 knockout mice. We found mutations in the insulin receptor substrate 4 (IRS4) gene in two pairs of brothers with CeH (one nonsense, one frameshift). Sequencing of IRS4 in 12 unrelated CeH cases negative for variants in known genes yielded three frameshift mutations (two novel) in three patients and one male sibling. All male carriers (n=8) had CeH with plasma free thyroxine concentrations below the reference interval. MRI of the hypothalamus and pituitary showed no structural abnormalities (n=12). 24-hour thyroid-stimulating hormone (TSH) secretion profiles in two adult male patients showed decreased basal, pulsatile and total TSH secretion. IRS4 mRNA was expressed in human hypothalamic nuclei, including the paraventricular nucleus, and in the pituitary gland. Female knockout mice showed decreased pituitary Tshb mRNA levels but had unchanged serum thyroid hormone concentrations. Mutations in IRS4 are associated with isolated CeH in male carriers. As IRS4 is involved in leptin signalling, the phenotype may be related to disrupted leptin signalling. © Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
Didier Raoult - One of the best experts on this subject based on the ideXlab platform.
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characterization of a new spotted fever group rickettsia detected in ixodes ricinus acari ixodidae collected in slovakia
Journal of Medical Entomology, 2000Co-Authors: Z Sekeyova, Pierreedouard Fournier, J řehacek, Didier RaoultAbstract:Abstract Two previously undescribed rickettsiae were detected in Ixodes ricinus Ricketts by polymerase chain reaction. Ixodes ricinus Slovakia (IRS)3 and IRS4 were identified in ticks collected in northeastern and southwestern Slovakia, respectively. Sequences of the 16S rRNA citrate synthase (gltA) and outer membrane protein rOmpA (ompA) encoding genes of both strains were nearly identical but were distinct from those of all other known rickettsiae. Phylogenetic relationships inferred from the comparison of these sequences with those of other members of the genus Rickettsia indicate that IRS3 and IRS4 constitute a new rickettsial genotype and form a separate cluster among the spotted fever group rickettsiae.
