Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1997 Nov 1;100(9):2158–2169. doi: 10.1172/JCI119752

Angiotensin II inhibits insulin signaling in aortic smooth muscle cells at multiple levels. A potential role for serine phosphorylation in insulin/angiotensin II crosstalk.

F Folli 1, C R Kahn 1, H Hansen 1, J L Bouchie 1, E P Feener 1
PMCID: PMC508410  PMID: 9410892

Abstract

To investigate potential interactions between angiotensin II (AII) and the insulin signaling system in the vasculature, insulin and AII regulation of insulin receptor substrate-1 (IRS-1) phosphorylation and phosphatidylinositol (PI) 3-kinase activation were examined in rat aortic smooth muscle cells. Pretreatment of cells with AII inhibited insulin-stimulated PI 3-kinase activity associated with IRS-1 by 60%. While AII did not impair insulin-stimulated tyrosine phosphorylation of the insulin receptor (IR) beta-subunit, it decreased insulin-stimulated tyrosine phosphorylation of IRS-1 by 50%. AII inhibited the insulin-stimulated association between IRS-1 and the p85 subunit of PI 3-kinase by 30-50% in a dose-dependent manner. This inhibitory effect of AII on IRS-1/PI 3-kinase association was blocked by the AII receptor antagonist saralasin, but not by AT1 antagonist losartan or AT2 antagonist PD123319. AII increased the serine phosphorylation of both the IR beta-subunit and IRS-1. In vitro binding experiments showed that autophosphorylation increased IR binding to IRS-1 from control cells by 2.5-fold versus 1.2-fold for IRS-1 from AII-stimulated cells, suggesting that AII stimulation reduces IRS-1's ability to associate with activated IR. In addition, AII increased p85 serine phosphorylation, inhibited the total pool of p85 associated PI 3-kinase activity, and decreased levels of the p50/p55 regulatory subunit of PI 3-kinase. These results suggest that activation of the renin-angiotensin system may lead to insulin resistance in the vasculature.

Full Text

The Full Text of this article is available as a PDF (1.3 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Antonetti D. A., Algenstaedt P., Kahn C. R. Insulin receptor substrate 1 binds two novel splice variants of the regulatory subunit of phosphatidylinositol 3-kinase in muscle and brain. Mol Cell Biol. 1996 May;16(5):2195–2203. doi: 10.1128/mcb.16.5.2195. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Araki E., Lipes M. A., Patti M. E., Brüning J. C., Haag B., 3rd, Johnson R. S., Kahn C. R. Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene. Nature. 1994 Nov 10;372(6502):186–190. doi: 10.1038/372186a0. [DOI] [PubMed] [Google Scholar]
  3. Backer J. M., Myers M. G., Jr, Shoelson S. E., Chin D. J., Sun X. J., Miralpeix M., Hu P., Margolis B., Skolnik E. Y., Schlessinger J. Phosphatidylinositol 3'-kinase is activated by association with IRS-1 during insulin stimulation. EMBO J. 1992 Sep;11(9):3469–3479. doi: 10.1002/j.1460-2075.1992.tb05426.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Banskota N. K., Taub R., Zellner K., Olsen P., King G. L. Characterization of induction of protooncogene c-myc and cellular growth in human vascular smooth muscle cells by insulin and IGF-I. Diabetes. 1989 Jan;38(1):123–129. doi: 10.2337/diab.38.1.123. [DOI] [PubMed] [Google Scholar]
  5. Bell L., Luthringer D. J., Madri J. A., Warren S. L. Autocrine angiotensin system regulation of bovine aortic endothelial cell migration and plasminogen activator involves modulation of proto-oncogene pp60c-src expression. J Clin Invest. 1992 Jan;89(1):315–320. doi: 10.1172/JCI115578. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Caro J. F., Ittoop O., Pories W. J., Meelheim D., Flickinger E. G., Thomas F., Jenquin M., Silverman J. F., Khazanie P. G., Sinha M. K. Studies on the mechanism of insulin resistance in the liver from humans with noninsulin-dependent diabetes. Insulin action and binding in isolated hepatocytes, insulin receptor structure, and kinase activity. J Clin Invest. 1986 Jul;78(1):249–258. doi: 10.1172/JCI112558. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Carpenter C. L., Auger K. R., Duckworth B. C., Hou W. M., Schaffhausen B., Cantley L. C. A tightly associated serine/threonine protein kinase regulates phosphoinositide 3-kinase activity. Mol Cell Biol. 1993 Mar;13(3):1657–1665. doi: 10.1128/mcb.13.3.1657. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cheatham B., Vlahos C. J., Cheatham L., Wang L., Blenis J., Kahn C. R. Phosphatidylinositol 3-kinase activation is required for insulin stimulation of pp70 S6 kinase, DNA synthesis, and glucose transporter translocation. Mol Cell Biol. 1994 Jul;14(7):4902–4911. doi: 10.1128/mcb.14.7.4902. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Chung J., Grammer T. C., Lemon K. P., Kazlauskas A., Blenis J. PDGF- and insulin-dependent pp70S6k activation mediated by phosphatidylinositol-3-OH kinase. Nature. 1994 Jul 7;370(6484):71–75. doi: 10.1038/370071a0. [DOI] [PubMed] [Google Scholar]
  10. Daemen M. J., Lombardi D. M., Bosman F. T., Schwartz S. M. Angiotensin II induces smooth muscle cell proliferation in the normal and injured rat arterial wall. Circ Res. 1991 Feb;68(2):450–456. doi: 10.1161/01.res.68.2.450. [DOI] [PubMed] [Google Scholar]
  11. Daub H., Weiss F. U., Wallasch C., Ullrich A. Role of transactivation of the EGF receptor in signalling by G-protein-coupled receptors. Nature. 1996 Feb 8;379(6565):557–560. doi: 10.1038/379557a0. [DOI] [PubMed] [Google Scholar]
  12. Dhand R., Hiles I., Panayotou G., Roche S., Fry M. J., Gout I., Totty N. F., Truong O., Vicendo P., Yonezawa K. PI 3-kinase is a dual specificity enzyme: autoregulation by an intrinsic protein-serine kinase activity. EMBO J. 1994 Feb 1;13(3):522–533. doi: 10.1002/j.1460-2075.1994.tb06290.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Diet F., Pratt R. E., Berry G. J., Momose N., Gibbons G. H., Dzau V. J. Increased accumulation of tissue ACE in human atherosclerotic coronary artery disease. Circulation. 1996 Dec 1;94(11):2756–2767. doi: 10.1161/01.cir.94.11.2756. [DOI] [PubMed] [Google Scholar]
  14. Dixon B. S., Sharma R. V., Dickerson T., Fortune J. Bradykinin and angiotensin II: activation of protein kinase C in arterial smooth muscle. Am J Physiol. 1994 May;266(5 Pt 1):C1406–C1420. doi: 10.1152/ajpcell.1994.266.5.C1406. [DOI] [PubMed] [Google Scholar]
  15. Duff J. L., Marrero M. B., Paxton W. G., Charles C. H., Lau L. F., Bernstein K. E., Berk B. C. Angiotensin II induces 3CH134, a protein-tyrosine phosphatase, in vascular smooth muscle cells. J Biol Chem. 1993 Dec 15;268(35):26037–26040. [PubMed] [Google Scholar]
  16. Dzau V. J. Cell biology and genetics of angiotensin in cardiovascular disease. J Hypertens Suppl. 1994 Jul;12(4):S3–10. [PubMed] [Google Scholar]
  17. Eck M. J., Dhe-Paganon S., Trüb T., Nolte R. T., Shoelson S. E. Structure of the IRS-1 PTB domain bound to the juxtamembrane region of the insulin receptor. Cell. 1996 May 31;85(5):695–705. doi: 10.1016/s0092-8674(00)81236-2. [DOI] [PubMed] [Google Scholar]
  18. Eguchi S., Matsumoto T., Motley E. D., Utsunomiya H., Inagami T. Identification of an essential signaling cascade for mitogen-activated protein kinase activation by angiotensin II in cultured rat vascular smooth muscle cells. Possible requirement of Gq-mediated p21ras activation coupled to a Ca2+/calmodulin-sensitive tyrosine kinase. J Biol Chem. 1996 Jun 14;271(24):14169–14175. doi: 10.1074/jbc.271.24.14169. [DOI] [PubMed] [Google Scholar]
  19. Feener E. P., Backer J. M., King G. L., Wilden P. A., Sun X. J., Kahn C. R., White M. F. Insulin stimulates serine and tyrosine phosphorylation in the juxtamembrane region of the insulin receptor. J Biol Chem. 1993 May 25;268(15):11256–11264. [PubMed] [Google Scholar]
  20. Feener E. P., Northrup J. M., Aiello L. P., King G. L. Angiotensin II induces plasminogen activator inhibitor-1 and -2 expression in vascular endothelial and smooth muscle cells. J Clin Invest. 1995 Mar;95(3):1353–1362. doi: 10.1172/JCI117786. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Ferrannini E., Buzzigoli G., Bonadonna R., Giorico M. A., Oleggini M., Graziadei L., Pedrinelli R., Brandi L., Bevilacqua S. Insulin resistance in essential hypertension. N Engl J Med. 1987 Aug 6;317(6):350–357. doi: 10.1056/NEJM198708063170605. [DOI] [PubMed] [Google Scholar]
  22. Folli F., Saad M. J., Backer J. M., Kahn C. R. Insulin stimulation of phosphatidylinositol 3-kinase activity and association with insulin receptor substrate 1 in liver and muscle of the intact rat. J Biol Chem. 1992 Nov 5;267(31):22171–22177. [PubMed] [Google Scholar]
  23. Folli F., Saad M. J., Backer J. M., Kahn C. R. Regulation of phosphatidylinositol 3-kinase activity in liver and muscle of animal models of insulin-resistant and insulin-deficient diabetes mellitus. J Clin Invest. 1993 Oct;92(4):1787–1794. doi: 10.1172/JCI116768. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Garg R., Yusuf S. Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. Collaborative Group on ACE Inhibitor Trials. JAMA. 1995 May 10;273(18):1450–1456. [PubMed] [Google Scholar]
  25. Haffner S. M., Stern M. P., Hazuda H. P., Mitchell B. D., Patterson J. K. Cardiovascular risk factors in confirmed prediabetic individuals. Does the clock for coronary heart disease start ticking before the onset of clinical diabetes? JAMA. 1990 Jun 6;263(21):2893–2898. doi: 10.1001/jama.263.21.2893. [DOI] [PubMed] [Google Scholar]
  26. Hamdan A. D., Quist W. C., Gagne J. B., Feener E. P. Angiotensin-converting enzyme inhibition suppresses plasminogen activator inhibitor-1 expression in the neointima of balloon-injured rat aorta. Circulation. 1996 Mar 15;93(6):1073–1078. doi: 10.1161/01.cir.93.6.1073. [DOI] [PubMed] [Google Scholar]
  27. Hotamisligil G. S., Peraldi P., Budavari A., Ellis R., White M. F., Spiegelman B. M. IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. Science. 1996 Feb 2;271(5249):665–668. doi: 10.1126/science.271.5249.665. [DOI] [PubMed] [Google Scholar]
  28. Howard G., O'Leary D. H., Zaccaro D., Haffner S., Rewers M., Hamman R., Selby J. V., Saad M. F., Savage P., Bergman R. Insulin sensitivity and atherosclerosis. The Insulin Resistance Atherosclerosis Study (IRAS) Investigators. Circulation. 1996 May 15;93(10):1809–1817. doi: 10.1161/01.cir.93.10.1809. [DOI] [PubMed] [Google Scholar]
  29. Inukai K., Anai M., Van Breda E., Hosaka T., Katagiri H., Funaki M., Fukushima Y., Ogihara T., Yazaki Y., Kikuchi A novel 55-kDa regulatory subunit for phosphatidylinositol 3-kinase structurally similar to p55PIK Is generated by alternative splicing of the p85alpha gene. J Biol Chem. 1996 Mar 8;271(10):5317–5320. doi: 10.1074/jbc.271.10.5317. [DOI] [PubMed] [Google Scholar]
  30. Jawien A., Bowen-Pope D. F., Lindner V., Schwartz S. M., Clowes A. W. Platelet-derived growth factor promotes smooth muscle migration and intimal thickening in a rat model of balloon angioplasty. J Clin Invest. 1992 Feb;89(2):507–511. doi: 10.1172/JCI115613. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Kelly K. L., Ruderman N. B. Insulin-stimulated phosphatidylinositol 3-kinase. Association with a 185-kDa tyrosine-phosphorylated protein (IRS-1) and localization in a low density membrane vesicle. J Biol Chem. 1993 Feb 25;268(6):4391–4398. [PubMed] [Google Scholar]
  32. Kim S., Kawamura M., Wanibuchi H., Ohta K., Hamaguchi A., Omura T., Yukimura T., Miura K., Iwao H. Angiotensin II type 1 receptor blockade inhibits the expression of immediate-early genes and fibronectin in rat injured artery. Circulation. 1995 Jul 1;92(1):88–95. doi: 10.1161/01.cir.92.1.88. [DOI] [PubMed] [Google Scholar]
  33. Klippel A., Escobedo J. A., Fantl W. J., Williams L. T. The C-terminal SH2 domain of p85 accounts for the high affinity and specificity of the binding of phosphatidylinositol 3-kinase to phosphorylated platelet-derived growth factor beta receptor. Mol Cell Biol. 1992 Apr;12(4):1451–1459. doi: 10.1128/mcb.12.4.1451. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Lam K., Carpenter C. L., Ruderman N. B., Friel J. C., Kelly K. L. The phosphatidylinositol 3-kinase serine kinase phosphorylates IRS-1. Stimulation by insulin and inhibition by Wortmannin. J Biol Chem. 1994 Aug 12;269(32):20648–20652. [PubMed] [Google Scholar]
  35. Linseman D. A., Benjamin C. W., Jones D. A. Convergence of angiotensin II and platelet-derived growth factor receptor signaling cascades in vascular smooth muscle cells. J Biol Chem. 1995 May 26;270(21):12563–12568. doi: 10.1074/jbc.270.21.12563. [DOI] [PubMed] [Google Scholar]
  36. Marrero M. B., Schieffer B., Paxton W. G., Heerdt L., Berk B. C., Delafontaine P., Bernstein K. E. Direct stimulation of Jak/STAT pathway by the angiotensin II AT1 receptor. Nature. 1995 May 18;375(6528):247–250. doi: 10.1038/375247a0. [DOI] [PubMed] [Google Scholar]
  37. Mothe I., Van Obberghen E. Phosphorylation of insulin receptor substrate-1 on multiple serine residues, 612, 632, 662, and 731, modulates insulin action. J Biol Chem. 1996 May 10;271(19):11222–11227. doi: 10.1074/jbc.271.19.11222. [DOI] [PubMed] [Google Scholar]
  38. Murphy T. J., Alexander R. W., Griendling K. K., Runge M. S., Bernstein K. E. Isolation of a cDNA encoding the vascular type-1 angiotensin II receptor. Nature. 1991 May 16;351(6323):233–236. doi: 10.1038/351233a0. [DOI] [PubMed] [Google Scholar]
  39. Myers M. G., Jr, White M. F. Insulin signal transduction and the IRS proteins. Annu Rev Pharmacol Toxicol. 1996;36:615–658. doi: 10.1146/annurev.pa.36.040196.003151. [DOI] [PubMed] [Google Scholar]
  40. Pillay T. S., Xiao S., Olefsky J. M. Glucose-induced phosphorylation of the insulin receptor. Functional effects and characterization of phosphorylation sites. J Clin Invest. 1996 Feb 1;97(3):613–620. doi: 10.1172/JCI118457. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Powell J. S., Clozel J. P., Müller R. K., Kuhn H., Hefti F., Hosang M., Baumgartner H. R. Inhibitors of angiotensin-converting enzyme prevent myointimal proliferation after vascular injury. Science. 1989 Jul 14;245(4914):186–188. doi: 10.1126/science.2526370. [DOI] [PubMed] [Google Scholar]
  42. Raccah D., Pettenuzzo-Mollo M., Provendier O., Boucher L., Cozic J. A., Gorlier R., Huin P., Sicard J., Vague P. Comparison of the effects of captopril and nicardipine on insulin sensitivity and thrombotic profile in patients with hypertension and android obesity. CaptISM Study Group. Captopril Insulin Sensitivity Multicenter Study Group. Am J Hypertens. 1994 Aug;7(8):731–738. doi: 10.1093/ajh/7.8.731. [DOI] [PubMed] [Google Scholar]
  43. Rakugi H., Jacob H. J., Krieger J. E., Ingelfinger J. R., Pratt R. E. Vascular injury induces angiotensinogen gene expression in the media and neointima. Circulation. 1993 Jan;87(1):283–290. doi: 10.1161/01.cir.87.1.283. [DOI] [PubMed] [Google Scholar]
  44. Rakugi H., Kim D. K., Krieger J. E., Wang D. S., Dzau V. J., Pratt R. E. Induction of angiotensin converting enzyme in the neointima after vascular injury. Possible role in restenosis. J Clin Invest. 1994 Jan;93(1):339–346. doi: 10.1172/JCI116965. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Rameh L. E., Chen C. S., Cantley L. C. Phosphatidylinositol (3,4,5)P3 interacts with SH2 domains and modulates PI 3-kinase association with tyrosine-phosphorylated proteins. Cell. 1995 Dec 1;83(5):821–830. doi: 10.1016/0092-8674(95)90195-7. [DOI] [PubMed] [Google Scholar]
  46. Regitz-Zagrosek V., Neuss M., Holzmeister J., Warnecke C., Fleck E. Molecular biology of angiotensin receptors and their role in human cardiovascular disease. J Mol Med (Berl) 1996 May;74(5):233–251. doi: 10.1007/BF00196577. [DOI] [PubMed] [Google Scholar]
  47. Ridray S., Heudes D., Michel O., Penicaud L., Ktorza A. Increased SMC proliferation after endothelial injury in hyperinsulinemic obese Zucker rats. Am J Physiol. 1994 Nov;267(5 Pt 2):H1976–H1983. doi: 10.1152/ajpheart.1994.267.5.H1976. [DOI] [PubMed] [Google Scholar]
  48. Rose D. W., Saltiel A. R., Majumdar M., Decker S. J., Olefsky J. M. Insulin receptor substrate 1 is required for insulin-mediated mitogenic signal transduction. Proc Natl Acad Sci U S A. 1994 Jan 18;91(2):797–801. doi: 10.1073/pnas.91.2.797. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Saad M. J., Velloso L. A., Carvalho C. R. Angiotensin II induces tyrosine phosphorylation of insulin receptor substrate 1 and its association with phosphatidylinositol 3-kinase in rat heart. Biochem J. 1995 Sep 15;310(Pt 3):741–744. doi: 10.1042/bj3100741. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Scherrer U., Randin D., Vollenweider P., Vollenweider L., Nicod P. Nitric oxide release accounts for insulin's vascular effects in humans. J Clin Invest. 1994 Dec;94(6):2511–2515. doi: 10.1172/JCI117621. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Schorb W., Peeler T. C., Madigan N. N., Conrad K. M., Baker K. M. Angiotensin II-induced protein tyrosine phosphorylation in neonatal rat cardiac fibroblasts. J Biol Chem. 1994 Jul 29;269(30):19626–19632. [PubMed] [Google Scholar]
  52. Shieh S. M., Sheu W. H., Shen D. D., Fuh M. M., Jeng C. Y., Jeng J. R., Chen Y. D., Reaven G. M. Improvement in metabolic risk factors for coronary heart disease associated with cilazapril treatment. Am J Hypertens. 1992 Aug;5(8):506–510. doi: 10.1093/ajh/5.8.506. [DOI] [PubMed] [Google Scholar]
  53. Steinberg H. O., Brechtel G., Johnson A., Fineberg N., Baron A. D. Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent. A novel action of insulin to increase nitric oxide release. J Clin Invest. 1994 Sep;94(3):1172–1179. doi: 10.1172/JCI117433. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Stoyanov B., Volinia S., Hanck T., Rubio I., Loubtchenkov M., Malek D., Stoyanova S., Vanhaesebroeck B., Dhand R., Nürnberg B. Cloning and characterization of a G protein-activated human phosphoinositide-3 kinase. Science. 1995 Aug 4;269(5224):690–693. doi: 10.1126/science.7624799. [DOI] [PubMed] [Google Scholar]
  55. Sun X. J., Pons S., Asano T., Myers M. G., Jr, Glasheen E., White M. F. The Fyn tyrosine kinase binds Irs-1 and forms a distinct signaling complex during insulin stimulation. J Biol Chem. 1996 May 3;271(18):10583–10587. doi: 10.1074/jbc.271.18.10583. [DOI] [PubMed] [Google Scholar]
  56. Sun X. J., Rothenberg P., Kahn C. R., Backer J. M., Araki E., Wilden P. A., Cahill D. A., Goldstein B. J., White M. F. Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein. Nature. 1991 Jul 4;352(6330):73–77. doi: 10.1038/352073a0. [DOI] [PubMed] [Google Scholar]
  57. Sun X. J., Wang L. M., Zhang Y., Yenush L., Myers M. G., Jr, Glasheen E., Lane W. S., Pierce J. H., White M. F. Role of IRS-2 in insulin and cytokine signalling. Nature. 1995 Sep 14;377(6545):173–177. doi: 10.1038/377173a0. [DOI] [PubMed] [Google Scholar]
  58. Takayama S., White M. F., Kahn C. R. Phorbol ester-induced serine phosphorylation of the insulin receptor decreases its tyrosine kinase activity. J Biol Chem. 1988 Mar 5;263(7):3440–3447. [PubMed] [Google Scholar]
  59. Tamemoto H., Kadowaki T., Tobe K., Yagi T., Sakura H., Hayakawa T., Terauchi Y., Ueki K., Kaburagi Y., Satoh S. Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1. Nature. 1994 Nov 10;372(6502):182–186. doi: 10.1038/372182a0. [DOI] [PubMed] [Google Scholar]
  60. Tanti J. F., Grémeaux T., Van Obberghen E., Le Marchand-Brustel Y. Insulin receptor substrate 1 is phosphorylated by the serine kinase activity of phosphatidylinositol 3-kinase. Biochem J. 1994 Nov 15;304(Pt 1):17–21. doi: 10.1042/bj3040017. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Tanti J. F., Grémeaux T., van Obberghen E., Le Marchand-Brustel Y. Serine/threonine phosphorylation of insulin receptor substrate 1 modulates insulin receptor signaling. J Biol Chem. 1994 Feb 25;269(8):6051–6057. [PubMed] [Google Scholar]
  62. Torlone E., Britta M., Rambotti A. M., Perriello G., Santeusanio F., Brunetti P., Bolli G. B. Improved insulin action and glycemic control after long-term angiotensin-converting enzyme inhibition in subjects with arterial hypertension and type II diabetes. Diabetes Care. 1993 Oct;16(10):1347–1355. doi: 10.2337/diacare.16.10.1347. [DOI] [PubMed] [Google Scholar]
  63. Velloso L. A., Folli F., Sun X. J., White M. F., Saad M. J., Kahn C. R. Cross-talk between the insulin and angiotensin signaling systems. Proc Natl Acad Sci U S A. 1996 Oct 29;93(22):12490–12495. doi: 10.1073/pnas.93.22.12490. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Wan Y., Kurosaki T., Huang X. Y. Tyrosine kinases in activation of the MAP kinase cascade by G-protein-coupled receptors. Nature. 1996 Apr 11;380(6574):541–544. doi: 10.1038/380541a0. [DOI] [PubMed] [Google Scholar]
  65. Weber H., Taylor D. S., Molloy C. J. Angiotensin II induces delayed mitogenesis and cellular proliferation in rat aortic smooth muscle cells. Correlation with the expression of specific endogenous growth factors and reversal by suramin. J Clin Invest. 1994 Feb;93(2):788–798. doi: 10.1172/JCI117033. [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. White M. F., Kahn C. R. The insulin signaling system. J Biol Chem. 1994 Jan 7;269(1):1–4. [PubMed] [Google Scholar]
  67. White M. F., Livingston J. N., Backer J. M., Lauris V., Dull T. J., Ullrich A., Kahn C. R. Mutation of the insulin receptor at tyrosine 960 inhibits signal transmission but does not affect its tyrosine kinase activity. Cell. 1988 Aug 26;54(5):641–649. doi: 10.1016/s0092-8674(88)80008-4. [DOI] [PubMed] [Google Scholar]
  68. Wolf G., Trüb T., Ottinger E., Groninga L., Lynch A., White M. F., Miyazaki M., Lee J., Shoelson S. E. PTB domains of IRS-1 and Shc have distinct but overlapping binding specificities. J Biol Chem. 1995 Nov 17;270(46):27407–27410. doi: 10.1074/jbc.270.46.27407. [DOI] [PubMed] [Google Scholar]
  69. Zavaroni I., Bonora E., Pagliara M., Dall'Aglio E., Luchetti L., Buonanno G., Bonati P. A., Bergonzani M., Gnudi L., Passeri M. Risk factors for coronary artery disease in healthy persons with hyperinsulinemia and normal glucose tolerance. N Engl J Med. 1989 Mar 16;320(11):702–706. doi: 10.1056/NEJM198903163201105. [DOI] [PubMed] [Google Scholar]
  70. Zeng G., Quon M. J. Insulin-stimulated production of nitric oxide is inhibited by wortmannin. Direct measurement in vascular endothelial cells. J Clin Invest. 1996 Aug 15;98(4):894–898. doi: 10.1172/JCI118871. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES