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Protein & Peptide Letters

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ISSN (Print): 0929-8665
ISSN (Online): 1875-5305

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Research Article

Phosphorylated and O-GlcNAc Modified IRS-1 (Ser1101) and -2 (Ser1149) Contribute to Human Diabetes Type II

Author(s): Afshan Kaleem*, Sabahat Javed, Nayab Rehman, Roheena Abdullah, Mehwish Iqtedar, Mohammad Nauman Aftab, Daniel C. Hoessli and Ikram-Ul Haq

Volume 28, Issue 3, 2021

Published on: 13 August, 2020

Page: [333 - 339] Pages: 7

DOI: 10.2174/0929866527666200813210407

Price: $65

Abstract

Background: The prevalence of the chronic metabolic disorder Type 2 diabetes mellitus (T2DM) is increasing steadily, and has even turned into an epidemic in some countries. T2DM results from defective responses to insulin and obesity is a major factor behind insulin resistance in T2DM. Insulin receptor substrate (IRS) proteins are adaptor proteins in the insulin receptor signalling pathway. The insulin signalling is controlled through tyrosine phosphorylation of IRS-1 and IRS-2, and dysregulation of IRS proteins signalling may lead to glucose intolerance and eventually insulin resistance.

Objective: In this work, we suggest that both glycosylation (O-GlcNAc modification) and phosphorylation of IRS-1 and -2 are involved in the pathogenesis of T2DM.

Methods: Phosphorylation and O-GlcNAc modifications (Ser1101 in IRS-1 and Ser1149 in IRS-2) proteins were determined experimentally by sandwich ELISA with specific antibodies and with bioinformatics tools.

Results: When IRS-1 (on Ser1101) and IRS-2 (Ser1149) become glycosylated following an increase in UDP-GlcNAc pools, it may contribute to insulin resistance. Whereas when the same (IRS-1 on Ser1101 and IRS-2 on Ser1149) are phosphorylated, the insulin signalling is inhibited.

Discussion: In this work OGlcNAc-modified proteins were specifically detected using O-Glc- NAc-specific antibodies, suggesting that elevated levels of O-GlcNAc-modified proteins are found, independently of their possible involvement in Advanced Glycation End products (AGEs).

Conclusion: This study suggests a mechanism, which is controlled by posttranslational modifications, and may contribute to the pathogenesis of type II diabetes.

Keywords: Insulin receptor substrates, phosphorylation, O-glycosylation, diabetes type II, insulin resistance, pathogenesis.

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[1]
Shulman, G.I. Cellular mechanisms of insulin resistance. J. Clin. Invest., 2000, 106(2), 171-176.
[http://dx.doi.org/10.1172/JCI10583] [PMID: 10903330]
[2]
DiMeglio, L.A.; Evans-Molina, C.; Oram, R.A. Type 1 diabetes. Lancet, 2018, 391(10138), 2449-2462.
[http://dx.doi.org/10.1016/S0140-6736(18)31320-5] [PMID: 29916386]
[3]
Stumvoll, M.; Goldstein, B.J.; van Haeften, T.W. Type 2 diabetes: principles of pathogenesis and therapy. Lancet, 2005, 365(9467), 1333-1346.
[http://dx.doi.org/10.1016/S0140-6736(05)61032-X] [PMID: 15823385]
[4]
Johnson, A.M.F.; Olefsky, J.M. The origins and drivers of insulin resistance. Cell, 2013, 152(4), 673-684.
[http://dx.doi.org/10.1016/j.cell.2013.01.041] [PMID: 23415219]
[5]
Shaw, L.M. The insulin receptor substrate (IRS) proteins: at the intersection of metabolism and cancer. Cell Cycle, 2011, 10(11), 1750-1756.
[http://dx.doi.org/10.4161/cc.10.11.15824] [PMID: 21597332]
[6]
Razzini, G.; Ingrosso, A.; Brancaccio, A.; Sciacchitano, S.; Esposito, D.L.; Falasca, M. Different subcellular localization and phosphoinositides binding of insulin receptor substrate protein pleckstrin homology domains. Mol. Endocrinol., 2000, 14(6), 823-836.
[http://dx.doi.org/10.1210/mend.14.6.0486] [PMID: 10847585]
[7]
Park, K.; Li, Q.; Rask-Madsen, C.; Mima, A.; Mizutani, K.; Winnay, J.; Maeda, Y.; D’Aquino, K.; White, M.F.; Feener, E.P.; King, G.L. Serine phosphorylation sites on IRS2 activated by angiotensin II and protein kinase C to induce selective insulin resistance in endothelial cells. Mol. Cell. Biol., 2013, 33(16), 3227-3241.
[http://dx.doi.org/10.1128/MCB.00506-13] [PMID: 23775122]
[8]
Zick, Y. Ser/Thr phosphorylation of IRS proteins: a molecular basis for insulin resistance. Sci. STKE, 2005, 2005(268), pe4.
[PMID: 15671481]
[9]
Copps, K.D.; White, M.F. Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2. Diabetologia, 2012, 55(10), 2565-2582.
[http://dx.doi.org/10.1007/s00125-012-2644-8] [PMID: 22869320]
[10]
Yang, X.; Qian, K. Protein O-GlcNAcylation: emerging mechanisms and functions. Nat. Rev. Mol. Cell Biol., 2017, 18(7), 452-465.
[http://dx.doi.org/10.1038/nrm.2017.22] [PMID: 28488703]
[11]
Nagel, A.K.; Ball, L.E. O-GlcNAc transferase and O-GlcNAcase: achieving target substrate specificity. Amino Acids, 2014, 46(10), 2305-2316.
[http://dx.doi.org/10.1007/s00726-014-1827-7] [PMID: 25173736]
[12]
Semba, R.D.; Huang, H.; Lutty, G.A.; Van Eyk, J.E.; Hart, G.W. The role of O-GlcNAc signaling in the pathogenesis of diabetic retinopathy. Proteomics Clin. Appl., 2014, 8(3-4), 218-231.
[http://dx.doi.org/10.1002/prca.201300076] [PMID: 24550151]
[13]
Ma, J.; Hart, G.W. Protein O-GlcNAcylation in diabetes and diabetic complications. Expert Rev. Proteomics, 2013, 10(4), 365-380.
[http://dx.doi.org/10.1586/14789450.2013.820536] [PMID: 23992419]
[14]
Whelan, S.A.; Dias, W.B.; Thiruneelakantapillai, L.; Lane, M.D.; Hart, G.W. Regulation of insulin receptor substrate 1 (IRS-1)/AKT kinase-mediated insulin signaling by O-Linked β-N-acetylglucosamine in 3T3-L1 adipocytes. J. Biol. Chem., 2010, 285(8), 5204-5211.
[http://dx.doi.org/10.1074/jbc.M109.077818] [PMID: 20018868]
[15]
Brahma, M.K.; Pepin, M.E.; Wende, A.R. My sweetheart is broken: Role of glucose in diabetic cardiomyopathy. Diabetes Metab. J., 2017, 41(1), 1-9.
[http://dx.doi.org/10.4093/dmj.2017.41.1.1] [PMID: 28236380]
[16]
Grote, C.W.; Morris, J.K.; Ryals, J.M.; Geiger, P.C.; Wright, D.E. Insulin receptor substrate 2 expression and involvement in neuronal insulin resistance in diabetic neuropathy. Exp. Diabetes Res., 2011, 2011, 212571.
[http://dx.doi.org/10.1155/2011/212571] [PMID: 21754917]
[17]
Alshammari, T.M.; Al-Hassan, A.A.; Hadda, T.B.; Aljofan, M. Comparison of different serum sample extraction methods and their suitability for mass spectrometry analysis. Saudi Pharm. J., 2015, 23(6), 689-697.
[http://dx.doi.org/10.1016/j.jsps.2015.01.023] [PMID: 26702265]
[18]
UniProt Consortium, T. UniProt: the universal protein knowledgebase. Nucleic Acids Res., 2018, 46(5), 2699.
[http://dx.doi.org/10.1093/nar/gky092] [PMID: 29425356]
[19]
Blom, N.; Gammeltoft, S.; Brunak, S. Sequence and structure-based prediction of eukaryotic protein phosphorylation sites. J. Mol. Biol., 1999, 294(5), 1351-1362.
[http://dx.doi.org/10.1006/jmbi.1999.3310] [PMID: 10600390]
[20]
Gupta, R.; Brunak, S. Prediction of glycosylation across the human proteome and the correlation to protein function. Pac. Symp. Biocomput., 2002, 7, 310-322.
[PMID: 11928486]
[21]
Altschul, S.F.; Gish, W.; Miller, W.; Myers, E.W.; Lipman, D.J. Basic local alignment search tool. J. Mol. Biol., 1990, 215(3), 403-410.
[http://dx.doi.org/10.1016/S0022-2836(05)80360-2] [PMID: 2231712]
[22]
Sievers, F.; Higgins, D.G. Clustal Omega for making accurate alignments of many protein sequences. Protein Sci., 2018, 27(1), 135-145.
[http://dx.doi.org/10.1002/pro.3290] [PMID: 28884485]
[23]
Sun, X.; Chen, Y.; Tan, J.; Qi, X. Serum IRS-1 acts as a novel biomarker for diagnosis in patients with nasopharyngeal carcinoma. Int. J. Clin. Exp. Pathol., 2018, 11(7), 3685-3690.
[PMID: 31949750]
[24]
Zeidan, Q.; Hart, G.W. The intersections between O-GlcNAcylation and phosphorylation: implications for multiple signaling pathways. J. Cell Sci., 2010, 123(Pt 1), 13-22.
[http://dx.doi.org/10.1242/jcs.053678] [PMID: 20016062]
[25]
Li, Y.; Soos, T.J.; Li, X.; Wu, J.; Degennaro, M.; Sun, X.; Littman, D.R.; Birnbaum, M.J.; Polakiewicz, R.D. Protein kinase C θ inhibits insulin signaling by phosphorylating IRS1 at Ser(1101). J. Biol. Chem., 2004, 279(44), 45304-45307.
[http://dx.doi.org/10.1074/jbc.C400186200] [PMID: 15364919]
[26]
Teo, C.F.; Wollaston-Hayden, E.E.; Wells, L. Hexosamine flux, the O-GlcNAc modification, and the development of insulin resistance in adipocytes. Mol. Cell. Endocrinol., 2010, 318(1-2), 44-53.
[http://dx.doi.org/10.1016/j.mce.2009.09.022] [PMID: 19799964]
[27]
Li, Y.; Zhou, X.; Zhai, Z.; Li, T. Co-occurring protein phosphorylation are functionally associated. PLOS Comput. Biol., 2017, 13(5), e1005502.
[http://dx.doi.org/10.1371/journal.pcbi.1005502] [PMID: 28459814]
[28]
Jahangir, Z.; Ahmad, W.; Shabbiri, K. Alternate phosphorylation/O-GlcNAc modification on human insulin IRSs: A road towards impaired insulin signaling in alzheimer and diabetes. Adv. Bioinforma., 2014, 2014, 324753.
[http://dx.doi.org/10.1155/2014/324753] [PMID: 25580119]
[29]
Mayer, C.M.; Belsham, D.D. Central insulin signaling is attenuated by long-term insulin exposure via insulin receptor substrate-1 serine phosphorylation, proteasomal degradation, and lysosomal insulin receptor degradation. Endocrinology, 2010, 151(1), 75-84.
[http://dx.doi.org/10.1210/en.2009-0838] [PMID: 19887566]
[30]
Griffin, M.E.; Marcucci, M.J.; Cline, G.W.; Bell, K.; Barucci, N.; Lee, D.; Goodyear, L.J.; Kraegen, E.W.; White, M.F.; Shulman, G.I. Free fatty acid-induced insulin resistance is associated with activation of protein kinase C θ and alterations in the insulin signaling cascade. Diabetes, 1999, 48(6), 1270-1274.
[http://dx.doi.org/10.2337/diabetes.48.6.1270] [PMID: 10342815]
[31]
Petersen, M.C.; Shulman, G.I. Mechanisms of insulin action and insulin resistance. Physiol. Rev., 2018, 98(4), 2133-2223.
[http://dx.doi.org/10.1152/physrev.00063.2017] [PMID: 30067154]
[32]
Szendroedi, J.; Yoshimura, T.; Phielix, E.; Koliaki, C.; Marcucci, M.; Zhang, D.; Jelenik, T.; Müller, J.; Herder, C.; Nowotny, P.; Shulman, G.I.; Roden, M. Role of diacylglycerol activation of PKCθ in lipid-induced muscle insulin resistance in humans. Proc. Natl. Acad. Sci. USA, 2014, 111(26), 9597-9602.
[http://dx.doi.org/10.1073/pnas.1409229111] [PMID: 24979806]
[33]
Vosseller, K.; Wells, L.; Lane, M.D.; Hart, G.W. Elevated nucleocytoplasmic glycosylation by O-GlcNAc results in insulin resistance associated with defects in Akt activation in 3T3-L1 adipocytes. Proc. Natl. Acad. Sci. USA, 2002, 99(8), 5313-5318.
[http://dx.doi.org/10.1073/pnas.072072399] [PMID: 11959983]
[34]
Kamemura, K.; Hayes, B.K.; Comer, F.I.; Hart, G.W. Dynamic interplay between O-glycosylation and O-phosphorylation of nucleocytoplasmic proteins: alternative glycosylation/ phosphorylation of THR-58, a known mutational hot spot of c-Myc in lymphomas, is regulated by mitogens. J. Biol. Chem., 2002, 277(21), 19229-19235.
[http://dx.doi.org/10.1074/jbc.M201729200] [PMID: 11904304]
[35]
Lefebvre, T.; Issad, T. 30 years old: O-GlcNAc reaches the age of reason - regulation of cell signaling and metabolism by O-GlcNAcylation. Front. Endocrinol. (Lausanne), 2015, 6, 17.
[http://dx.doi.org/10.3389/fendo.2015.00017] [PMID: 25709599]
[36]
Klein, A.L.; Berkaw, M.N.; Buse, M.G.; Ball, L.E. O-linked N-acetylglucosamine modification of insulin receptor substrate-1 occurs in close proximity to multiple SH2 domain binding motifs. Mol. Cell. Proteomics, 2009, 8(12), 2733-2745.
[http://dx.doi.org/10.1074/mcp.M900207-MCP200] [PMID: 19671924]
[37]
Park, S.Y.; Ryu, J.; Lee, W. O-GlcNAc modification on IRS-1 and Akt2 by PUGNAc inhibits their phosphorylation and induces insulin resistance in rat primary adipocytes. Exp. Mol. Med., 2005, 37(3), 220-229.
[http://dx.doi.org/10.1038/emm.2005.30] [PMID: 16000877]
[38]
Singh, V.P.; Bali, A.; Singh, N.; Jaggi, A.S. Advanced glycation end products and diabetic complications. Korean J. Physiol. Pharmacol., 2014, 18(1), 1-14.
[http://dx.doi.org/10.4196/kjpp.2014.18.1.1] [PMID: 24634591]
[39]
Ducheix, S.; Magré, J.; Cariou, B.; Prieur, X. Chronic O-GlcNAcylation and diabetic cardiomyopathy: The bitterness of glucose. Front. Endocrinol. (Lausanne), 2018, 9, 642.
[http://dx.doi.org/10.3389/fendo.2018.00642] [PMID: 30420836]
[40]
Taniguchi, N.; Miyoshi, E.; Gu, J.; Honke, K.; Matsumoto, A. Decoding sugar functions by identifying target glycoproteins. Curr. Opin. Struct. Biol., 2006, 16(5), 561-566.
[http://dx.doi.org/10.1016/j.sbi.2006.08.011] [PMID: 16971114]
[41]
Hart, G.W.; Slawson, C.; Ramirez-Correa, G.; Lagerlof, O. Cross talk between O-GlcNAcylation and phosphorylation: roles in signaling, transcription, and chronic disease. Annu. Rev. Biochem., 2011, 80, 825-858.
[http://dx.doi.org/10.1146/annurev-biochem-060608-102511] [PMID: 21391816]

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