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Angiotensin II modulates tyr-phosphorylation of IRS-4, an insulin receptor substrate, in rat liver membranes

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Abstract

Angiotensin II (Ang II), a major regulator of blood pressure, is also involved in the control of cellular proliferation and hypertrophy and might exhibit additional actions in vivo by modulating the signaling of other hormones. As hypertension and Insulin (Ins) resistance often coexist and are risk factors for cardiovascular diseases, Ang II and Insulin signaling cross-talk may have an important role in hypertension development. The effect of Ins on protein tyrosine phosphorylation was assayed in rat liver membrane preparations, a rich source of Ins receptors. Following stimulation, Ins (10−7 M) induced tyr-phosphorylation of different proteins. Insulin consistently induced tyr-phosphorylation of a 160 kDa protein (pp160) with maximum effect between 1 and 3 min. The pp160 protein was identified by anti-IRS-4 but not by anti-IRS-1 antibody. Pre-stimulation with Ang II (10−7 M) diminishes tyr-phosphorylation level of pp160/IRS-4 in a dose-dependent manner. Okadaic acid, the PP1A and PP2A Ser/Thr phosphatase inhibitor, increases pp160 phosphorylation induced by Ins and prevents the inhibitory effect of Ang II pre-stimulation. Genistein, a tyrosine kinase inhibitor, diminishes tyr-phosphorylation level of IRS-4. PI3K inhibitors Wortmanin and LY294002, both increase tyr-phosphorylation of IRS-4, either in the presence of Ins alone or combined with Ang II. These results suggest that Ins and Ang II modulate IRS-4 tyr-phosphorylation in a PI3K-dependent manner. In summary, we showed that Ins induces tyr-phosphorylation of IRS-4, an effect modulated by Ang II. Assays performed in the presence of different inhibitors points toward a PI3K involvement in this signaling pathway.

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References

  1. Velloso LA, Folli F, Sun XJ, White MF, Saad MJA: Crosstalk between the insulin and angiotensin signaling systems. Proc Nat Acad Sci USA 93: 12490–12495, 1996

    Article  PubMed  CAS  Google Scholar 

  2. Gutkind JS: The pathways connecting G Protein-coupled receptors to the nucleus through divergent mitogen-activated protein kinase cascade. J Biol Chem 273: 1839–1842, 1998

    Article  PubMed  CAS  Google Scholar 

  3. De Gasparo M, Catt KJ, Inagami T, Wright JW, Unger TH: International Union of Pharmacology. XXIII. The Angiotensin II Receptors. Pharmacol Rev 52: 415–472, 2000

    PubMed  Google Scholar 

  4. Gallinat S, Busche S, Raizada MK, Summers C: The Angiotensin II type 2 receptor: an enigma with multiple variations. Am J Physiol Endocrinol Metab 278: E357–E374, 2000

    PubMed  CAS  Google Scholar 

  5. Marrero MB, Paxton WG, Duff JL, Berk BC, Bernstein KE: Angiotensin II stimulates tyrosine phosphorylation of phospholipase C-gamma 1 in vascular smooth muscle cells. J Biol Chem 269: 10935–10939, 1994

    PubMed  CAS  Google Scholar 

  6. White MF, Kahn R: The insulin signaling system. J Biol Chem 269: 1–4, 1994.

    PubMed  CAS  Google Scholar 

  7. Giovannone B, Scaldaferri ML, Federici M, Porzio O, Lauro D, Fusco A, Sbraccia P, Borboni P, Lauro R, Sesti G: Insulin receptor substrate (IRS) transduction system: distinct overlapping signaling potential. Diabetes Metab Res Rev 16: 434–441, 2000

    Article  PubMed  CAS  Google Scholar 

  8. Ogihara T, Schin B, Anai, Katagiri H, Inukai K, Funaki M, Fukushima Y, Ishihara H, Takata K, Kikuchi M, Yazaki Y, Oka Y, Asano T: Insulin receptor substrate (IRS-2) is dephosphorylated more rapidly than IRS-1 via its association with phosphatidylinositol 3-kinase in skeletal muscle cells. J Biol Chem 272: 12868–12873, 1997

    Article  PubMed  CAS  Google Scholar 

  9. Lavan BE, Fantin VR, Chang ET, Lane WS, Keller, SR, Lienhard GE: A novel 160-kDa phosphotyrosine protein in insulin-treated embryonic kidney cells is a new member of the insulin receptor substrate family. J Biol Chem 272: 21403–21407, 1997

    Article  PubMed  CAS  Google Scholar 

  10. Fantin VR, Lavan BR, Wang Q, Jenkins NA, Gilbert DJ, Copeland NG, Keller SR, Lienhard GE: Cloning, tissue expression, and chromosomal location of de mouse insulin receptor substrate 4 Gene. Endocrinol 140: 1329–1337, 1999

    Article  CAS  Google Scholar 

  11. Cai D, Dhe-Paganono S, Melendez PA, Lee J, Shoelson SE: Two new substrates in insulin signaling, IRS5/DOK4 and IRS6/DOK5. J Biol Chem 278: 25323–25330, 2003

    Article  PubMed  CAS  Google Scholar 

  12. Ohne Y, Toyoshima Y, Kato H: Disruption of the availability of amino acids induces a rapid reduction of serine phosphorylation of insulin receptor subtrate-1 in vivo and in vitro. Biosci Biotechnol Biochem 69: 9889–998, 2005

    Article  Google Scholar 

  13. Malarkey K, Belham CM, Paul A, Graham A, McLees A, Scott PH, Plevin R: The regulation of tyrosine kinase signalling pathways by growth factor and G-protein-coupled receptors. Biochem J 309: 361–375, 1995

    PubMed  CAS  Google Scholar 

  14. Patiag D, Qu X, Gray S, Idris I, Wilkes M, Seale JP: Possible interactions between angiotensin II and insulin: effects on glucose and lipid metabolism in vivo and in vitro. J Endocrinol 167: 525–531, 2000

    Article  PubMed  CAS  Google Scholar 

  15. Ali MS, Schieffer B, Delafontaine P, Bernstein KE, Ling BN, Marrero M: Angiotensin II stimulates tyrosine phosphorylation and activation of insulin receptor sustrate 1 and protein–tyrosine phosphatase 1D in vascular smooth muscle cells. J Biol Chem 272: 12373–12379, 1997

    Article  PubMed  CAS  Google Scholar 

  16. Folli F, Kahn CR, Hansen H, Bouchie JL, Feener EP: Angiotensin II inhibits insulin signaling in aortic smooth muscle cells at multiple levels. J Clin Invest 100: 2158–2169, 1997

    Article  PubMed  CAS  Google Scholar 

  17. Senthil D, Faulkner JL, Choudhury GG, Abboud HE, Kasinath BS: Angiotensin II inhibits insulin-stimulated phosphorylation of eukaryotic initiation factor 4E-binding protein-1 in proximal tubular epithelial cells. Biochem J 360: 87–95, 2001

    Article  PubMed  CAS  Google Scholar 

  18. Elbaz N, Bedecs K, Masson M, Sutren M, Strosberg AD, Nahmias C: Functional trans-inactivation of insulin receptor kinase by growth-inhibitory angiotensin II AT2 receptor. Mol Endocrinol 14: 795–804, 2000

    Article  PubMed  CAS  Google Scholar 

  19. Cui TX, Nakagami H, Nahmias C, Shiuchi T, Takeda-Matsubara Y, Li JM, Wu L, Iwai M, Horiuchi M: Angiotensin II subtype 2 receptor activation inhibits insulin-induced phosphoinositide 3-kinase and Akt and induces apoptosis in PC12W cells. Mol Endocrinol 16: 2113–2123, 2002

    Article  PubMed  CAS  Google Scholar 

  20. Rother CI, Imai Y, Caruso M, Beguinot F, Formisano P, Accili D: Evidence that IRS-2 phosphorylation is required for insulin action in hepatocytes. J Biol Chem 273: 17491–17497, 1998

    Article  PubMed  CAS  Google Scholar 

  21. Alvarez SE, Fuentes LB, Ciuffo GM: Angiotensin II mediates tyr-dephosphorylation in rat fetal kidney membranes. Mol Cel Biochem 254: 137–143, 2003.

    Article  CAS  Google Scholar 

  22. De Luca JP, Garnache AK, Rufls J, Miller TB Jr: Wortmanin inhibits insulin-stimulated activation of protein phosphatase 1 in rat cardiomyocytes. Am J Physiol 276: H1520–H1526, 1999

    PubMed  Google Scholar 

  23. Schreyer S, Ledwig D, Rakatzi I, Klöting I, Eckel J: Insulin receptor substrate-4 is expressed in muscle tissue without acting as a substrate for the insulin receptor. Endocrinology 144: 1211–1218, 2003

    Article  PubMed  CAS  Google Scholar 

  24. Escribano O, Fernández-Moreno MD, Zueco JA, Menor C, Fueyo J, Ropero RM, Díaz-Laviada I, Román ID, Guijarro LG: Insulin Receptor Substrate-4 in quiescent rat hepatocytes and in regenerating rat liver. Hepatology 37: 1461–1469, 2003

    Article  PubMed  CAS  Google Scholar 

  25. Fantin VR, Keller SR, Lienhard GE, Wang L-M: Insulin receptor substrate 4 supports insulin- and interleukin 4-stimulated proliferation of hematopoietic cells. Biochem Biophys Res Commun, 260: 718–723, 1999

    Article  PubMed  CAS  Google Scholar 

  26. Fantin VR, Wang Q, Lienhard GE, Keller SR: Mice lacking insulin receptor substrate 4 exhibit mild effect in growth, reproduction, and glucose homeostasis. Am J Physiol Endocrinol Metab 278: E127–E133, 2000

    PubMed  CAS  Google Scholar 

  27. Tanti JF, Gual P, Grémeaux T, Gonzalez T, Barrès R, Le-Marchand-Brustel Y: Alteration in insulin action: role of IRS-1 serine phosphorylatikon in the retroregulation of insulin signalling. Ann Endocrinol 65: 43–48, 2004

    CAS  Google Scholar 

  28. Cengel KA, Freund GG: JAK1-dependent phosphorylation of Insulin receptor substrate-1 (IRS-1) is inhibited by IRS-1 Serine phosphorylation. J Biol Chem 274: 27969–27974, 1999

    Article  PubMed  CAS  Google Scholar 

  29. Le Marchand-Brustel Y, Gual P, Grèmeaux T, Gonzalez T, Barrés R, Tanti JF: Fatty acid-induced insulin resistance: role of insulin receptor substrate 1 serine phosphorylation in the retroregulation of insulin signalling. Biochem Soc Trans 31: 1152–1156, 2003

    Article  PubMed  Google Scholar 

  30. Um SH, Frigerio F, Watanabe M, Picard F, Joaquin M, Sticker M, Fumagalli S, Allegrini PR, Kozma SC, Auwerx J, Thomas G: Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature 431: 200–205, 2004

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Bioquímica Avanzada, Depto. Bioquímica y Cs. Biológicas. Facultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis, Ejército de los Andes, 950–5700, San Luis, Argentina

    Rodrigo S. Villarreal, Sergio E. Alvarez, Maximiliano Juri Ayub & Gladys M. Ciuffo

  2. Bioquímica Avanzada – Bloque I, Depto. de Bioquímica y Cs. Biológicas, Facultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis, Ejército de los Andes, 950–5700, San Luis, Argentina

    Gladys M. Ciuffo

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  1. Rodrigo S. Villarreal
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  2. Sergio E. Alvarez
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  3. Maximiliano Juri Ayub
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  4. Gladys M. Ciuffo
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Correspondence to Gladys M. Ciuffo.

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Villarreal, R.S., Alvarez, S.E., Ayub, M.J. et al. Angiotensin II modulates tyr-phosphorylation of IRS-4, an insulin receptor substrate, in rat liver membranes. Mol Cell Biochem 293, 35–46 (2006). https://doi.org/10.1007/s11010-006-2492-2

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  • DOI: https://doi.org/10.1007/s11010-006-2492-2

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