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Light regulation of the insulin receptor in the retina

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Abstract

The peptide hormone insulin binds its cognate cell-surface receptors to activate a coordinated biochemical-signaling network and to induce intracellular events. The retina is an integral part of the central nervous system and is known to contain insulin receptors, although their function is unknown. This article, describes recent studies that link the photobleaching of rhodopsin to tyrosine phosphorylation of the insulin receptor and subsequent activation of phosphoinositide 3-kinase (PI3K). We recently found a light-dependent increase in tyrosine phosphorylation of the insulin receptor-β-subunit (IRβ) and an increase in PI3K enzyme activity in isolated rod outer segments (ROS) and in anti-phosphotyrosine (PY) and anti-IRβ immunoprecipitates of retinal homogenates. The light effect, which was localized to photoreceptor neurons, is independent of insulin secretion. Our results suggest that light induces tyrosine phosphorylation of IRβ in outersegment membranes, which leads to the binding of p85 through its N-terminal SH2 domain and the generation of PI-3,4,5-P3. We suggest that the physiological role of this process may be to provide neuroprotection of the retina against light damage by activating proteins that protect against stress-induced apoptosis. The studies linking PI3K activation through tyrosine phosphorylation of IRβ now provide physiological relevance for the presence of these receptors in the retina.

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References

  1. Barritt G.J. (1992) Communication with Animal Cells. Oxford Science Publications, Oxford, United Kingdom.

    Google Scholar 

  2. Yan D., Schulte M.K., Bloom K.E. et al. (1999) Structural features of the ligand-binding domain of the serotonin 5HT3 receptor. J. Biol. Chem. 274, 5537–5541.

    Article  PubMed  CAS  Google Scholar 

  3. Schenk P.W. and Snaar-Jagalska B.E. (1999) Signal perception and transduction: the role of protein kinases. Biochim. Biophys. Acta 1449, 1–24.

    Article  PubMed  CAS  Google Scholar 

  4. Porter A.C. and Vaillancourt R.R. (1998) Tyrosine kinase receptor-activated signal transduction pathways which lead to oncogenesis. Oncogene 17, 1343–1352.

    Article  PubMed  CAS  Google Scholar 

  5. Hibi M. and Hirano T. (1998) Signal transduction through cytokine receptors. Int. Rev. Immunol. 17, 75–102.

    PubMed  CAS  Google Scholar 

  6. Weiss R.H. (1998) G protein-coupled receptor signalling in the kidney. Cell Signalling 10, 313–320.

    Article  PubMed  CAS  Google Scholar 

  7. Anand-Apte B. and Zetter B. (1997) Signaling mechanisms in growth factor-stimulated cell motility. Stem Cells 15, 259–267.

    Article  PubMed  CAS  Google Scholar 

  8. Zhou M., Sevilla L., Vallega G., et al. (1998) Insulin-dependent protein trafficking in skeletal muscle cells. Am. J. Physiol. 275, E187-E196.

    PubMed  CAS  Google Scholar 

  9. Girard D., Paquin R., and Beaulieu A.D. (1997) Responsiveness of human neutrophils to interleukin-4: induction of cytoskeletal rearrangements, de novo protein synthesis and delay of apoptosis. Biochem. J. 325(Pt 1), 147–153.

    PubMed  CAS  Google Scholar 

  10. Wulfing C., Rabinowitz J.D., Beeson C., et al. (1997) Kinetics and extent of T cell activation as measured with the calcium signal. J. Exp. Med. 185, 1815–1825.

    Article  PubMed  CAS  Google Scholar 

  11. Dragovich T., Rudin C.M., and Thompson C.B. (1998) Signal transduction pathways that regulate cell survival and cell death. Oncogene 17, 3207–3213.

    Article  PubMed  Google Scholar 

  12. Kazlauskas A. (1994) Receptor tyrosine kinases and their targets. Curr. Opin. Genet. Dev. 4, 5–14.

    Article  PubMed  CAS  Google Scholar 

  13. Josso N., di Clemente N. (1997) Serine/threonine kinase receptors and ligands. Curr. Opin. Genet. Dev. 7, 371–377.

    Article  PubMed  CAS  Google Scholar 

  14. White M.F. and Kahn C.R. (1994) The insulin signaling system. J. Biol. Chem. 269, 1–4.

    PubMed  CAS  Google Scholar 

  15. Whitehead J.P., Clark S.F., Urso B., et al. (2000) Signalling through the insulin receptor. Curr. Opin. Cell Biol. 12, 222–228.

    Article  PubMed  CAS  Google Scholar 

  16. Myers M.G., Jr. and White M.F. (1996) Insulin signal transduction and the IRS proteins. Annu. Rev. Pharmacol. Toxicol. 36, 615–658.

    Article  PubMed  CAS  Google Scholar 

  17. DeFronzo R.A., Bonadonna R.C., and Ferrannini E. (1992) Pathogenesis of NIDDM. A balanced overview. Diabetes Care 15, 318–368.

    Article  PubMed  CAS  Google Scholar 

  18. Van Horn D.J., Myers M.G., Jr., and Backer J.M. (1994) Direct activation of the phosphatidylinositol 3′-kinase by the insulin receptor. J. Biol. Chem. 269, 29–32.

    PubMed  Google Scholar 

  19. Backer J.M., Myers M.G., Jr., Shoelson S.E., et al. (1992) Phosphatidylinositol 3′-kinase is activated by association with IRS-1 during insulin stimulation. EMBO J. 11, 3469–3479.

    PubMed  CAS  Google Scholar 

  20. Kuhne M.R., Pawson T., Lienhard G.E., et al. (1993) The insulin receptor substrate 1 associates with the SH2-containing phosphotyrosine phosphatase Syp. J. Biol. Chem. 268, 11,479–11,481.

    CAS  Google Scholar 

  21. Skolnik E.Y., Batzer A., Li N., et al. (1993) The function of GRB2 in linking the insulin receptor to Ras signaling pathways. Science 260, 1953–1955.

    Article  PubMed  CAS  Google Scholar 

  22. Lee C.H., Li W., Nishimura R., et al. (1993) Nck associates with the SH2 domain-docking protein IRS-1 in insulin-stimulated cells. Proc. Natl. Acad. Sci. USA 90, 11,713–11,717.

    CAS  Google Scholar 

  23. Seino S., Seino M., and Bell G.I. (1990) Human insulin-receptor gene. Diabetes 39, 129–133.

    Article  PubMed  CAS  Google Scholar 

  24. Waldbillig R.J., Fletcher R.T., Chader G.J. et al (1987) Retinal insulin receptors. 1. Structural heterogeneity and functional characterization. Exp. Eye Res. 45, 823–835.

    Article  PubMed  CAS  Google Scholar 

  25. Waldbillig R.J., Fletcher R.T., Chader G.J., et al. (1987) Retinal insulin receptors. 2. Characterization and insulin-induced tyrosine kinase activity in bovine retinal rod outer segments. Exp. Eye Res. 45, 837–844.

    Article  PubMed  CAS  Google Scholar 

  26. Rosenzweig S.A., Zetterstrom C., and Benjamin A. (1990) Identification of retinal insulin receptors using site-specific antibodies to a carboxyl-terminal peptide of the human insulin receptor alpha-subunit. Up-regulation of neuronal insulin receptors in diabetes. J. Biol. Chem. 265, 18,030–18,034.

    CAS  Google Scholar 

  27. Zetterstrom C., Fang C., Benjamin A., et al. (1991) Characterization of a novel receptor in toad retina with dual specificity for insulin and insulin-like growth factor 1. J. Neurochem. 57, 1332–1339.

    Article  PubMed  CAS  Google Scholar 

  28. Hernandez-Sanchez C., Lopez-Carranza A., Alarcon C., et al. (1995) Autocrine/paracrine role of insulin-related growth factors in neurogenesis: local expression and effects on cell proliferation and differentiation in retina. Proc. Natl. Acad. Sci. USA 92, 9834–9838.

    Article  PubMed  CAS  Google Scholar 

  29. Hernandez-Sanchez C., Blakesley V., Kalebic T., et al. (1995) The role of the tyrosine kinase domain of the insulin-like growth factor-1 receptor in intracellular signaling cellular proliferation, and tumorigenesis. J. Biol. Chem. 270, 29,176–29,181.

    CAS  Google Scholar 

  30. Hitchcock P.F., Otteson D.C., and Cirenza P.F. (2001) Expression of the insulin receptor in the retina of the goldfish. Investig. Ophthalmol. Vis. Sci. 42, 2125–2129.

    CAS  Google Scholar 

  31. Rodrigues M., Waldbillig R.J., Rajagopalan S., et al. (1988) Retinal insulin receptors: localization using a polyclonal anti-insulin receptor antibody. Brain Res. 443, 389–394.

    Article  PubMed  CAS  Google Scholar 

  32. Stella S.L., Jr., Bryson E.J., and Thoreson W.B. (2001) Insulin inhibits voltage-dependent calcium influx into rod photoreceptors. Neuroreport 12, 947–951.

    Article  PubMed  CAS  Google Scholar 

  33. Frasson M., Sahel J.A., Fabre M., et al. (1999) Retinitis pigmentosa: rod photoreceptor rescue by a calcium-channel blocker in the rd mouse. Nat. Med. 5, 1183–1187.

    Article  PubMed  CAS  Google Scholar 

  34. Barber A.J., Nakamura M., Wolpert E.B., et al. (2001) Insulin rescues retinal neurons from apoptosis by a phosphatidylinositol 3-kinase/Akt-mediated mechanism that reduces the activation of caspase-3. J. Biol. Chem. 276, 32,814–32,821.

    Article  CAS  Google Scholar 

  35. Marshall C.J. (1995) Specificity of receptor tyrosine kinase signaling: transient versus sustained extra-cellular signal-regulated kinase activation. Cell 80, 179–185.

    Article  PubMed  CAS  Google Scholar 

  36. Schlessinger J., Ullrich A. (1992) Growth factor signaling by receptor tyrosine kinases. Neuron 9, 383–391.

    Article  PubMed  CAS  Google Scholar 

  37. Ghalayini A.J., Guo X.X., Koutz C.A., et al. (1998) Light stimulates tyrosine phosphorylation of rat rod outer segments In vivo. Exp. Eye Res. 66, 817–821.

    Article  PubMed  CAS  Google Scholar 

  38. Bell M.W., Alvarez K., and Ghalayini A.J. (1999) Association of the tyrosine phosphatase SHP-2 with transducin-alpha and a 97-kDa tyrosine-phosphorylated protein in photoreceptor rod outer segments. J. Neurochem. 73, 2331–2340.

    Article  PubMed  CAS  Google Scholar 

  39. Bell M.W., Desai N., Guo X.X., et al. (2000) Tyrosine phosphorylation of the alpha subunit of transducin and its association with Src in photoreceptor rod outer segments. J. Neurochem. 75, 2006–2019.

    Article  PubMed  CAS  Google Scholar 

  40. Rajala R.V. and Anderson R.E. (2001) Interaction of the insulin receptor beta-subunit with phosphatidylinositol 3-kinase in bovine ROS. Investig. Ophthalmol. Vis. Sci. 42, 3110–3117.

    CAS  Google Scholar 

  41. Rajala R.V., McClellan M.E., Ash J.D., et al. (2002) In vivo regulation of phosphoinositide 3-kinase in retina through light-induced tyrosine phosphorylation of the insulin receptor beta-subunit. J. Biol. Chem. 277, 43,319–43,326.

    Article  CAS  Google Scholar 

  42. Carpenter C.L., Duckworth B.C., Auger K.R., et al. (1990) Purification and characterization of phosphoinositide 3-kinase from rat liver. J. Biol. Chem. 265, 19,704–19,711.

    CAS  Google Scholar 

  43. Dhand R., Hiles I., Panayotou G., et al. (1994) Pl 3-kinase is a dual specificity enzyme: autoregulation by an intrinsic protein-serine kinase activity. EMBO J. 13, 522–533.

    PubMed  CAS  Google Scholar 

  44. Skolnik E.Y., Margolis B., Mohammadi M., et al. (1991) Cloning of PI3 kinase-associated p85 utilizing a novel method for expression/cloning of target proteins for receptor tyrosine kinases. Cell 65, 83–90.

    Article  PubMed  CAS  Google Scholar 

  45. Fruman D.A., Meyers R.E., and Cantley L.C. (1998) Phosphoinositide kinases. Annu. Rev. Biochem. 67, 481–507.

    Article  PubMed  CAS  Google Scholar 

  46. Clement S., Krause U., Desmedt F., et al. (2001) The lipid phosphatase SHIP2 controls insulin sensitivity. Nature 409, 92–97.

    Article  PubMed  CAS  Google Scholar 

  47. Maehama T., Dixon J.E. (1999) PTEN: a tumour suppressor that functions as a phospholipid phosphatase. Trends Cell Biol. 9, 125–128.

    Article  PubMed  CAS  Google Scholar 

  48. Cantley L.C. (2002) The phosphoinositide 3-kinase pathway. Science 296, 1655–1657.

    Article  PubMed  CAS  Google Scholar 

  49. Kaplan D.R., Whitman M., Schaffhausen B., et al. (1987) Common elements in growth factor stimulation and oncogenic transformation: 85 kd phosphoprotein and phosphatidylinositol kinase activity. Cell 50, 1021–1029.

    Article  PubMed  CAS  Google Scholar 

  50. Kanagasundaram V., Jaworowski A., and Hamilton J.A. (1996) Association between phosphatidylinositol-3 kinase, Cbl and other tyrosine phosphorylated proteins in colony-stimulating factor-1-stimulated macrophages. Biochem. J. 320(Pt 1), 69–77.

    PubMed  CAS  Google Scholar 

  51. Pleiman C.M., Hertz W.M., and Cambier J.C. (1994) Activation of phosphatidylinositol-3′ kinase by Src-family kinase SH3 binding to the p85 subunit. Science 263, 1609–1612.

    Article  PubMed  CAS  Google Scholar 

  52. Soltoff S.P., Rabin S.L., Cantley L.C., et al. (1992) Nerve growth factor promotes the activation of phosphatidylinositol 3-kinase and its association with the trk tyrosine kinase. J. Biol. Chem. 267, 17,472–17,477.

    CAS  Google Scholar 

  53. Thomas J.W., Ellis B., Boerner R.J., et al. (1998) SH2-and SH3-mediated interactions between focal adhesion kinase and Src. J. Biol. Chem. 273, 577–583.

    Article  PubMed  CAS  Google Scholar 

  54. Kavanaugh W.M., Klippel A., Escobedo J.A., et al. (1992) Modification of the 85-kilodalton subunit of phosphatidylinositol-3 kinase in platelet-derived growth factor-stimulated cells. Mol. Cell Biol. 12, 3415–3424.

    PubMed  CAS  Google Scholar 

  55. Hayashi H., Miyake N., Kanai F., et al. (1991) Phosphorylation in vitro of the 85 kDa subunit of phosphatidylinositol 3-kinase and its possible activation by insulin receptor tyrosine kinase. Biochem. J. 280(Pt 3), 769–775.

    PubMed  CAS  Google Scholar 

  56. Fry M.J. (1994) Structure, regulation and function of phosphoinositide 3-kinases. Biochim. Biophys. Acta 1226, 237–268.

    PubMed  CAS  Google Scholar 

  57. Gesbert F., Garbay C., and Bertoglio J. (1998) Interleukin-2 stimulation induces tyrosine phosphorylation of p120-Cbl and CrkL and formation of multimolecular signaling complexes in T lymphocytes and natural killer cells. J. Biol. Chem. 273, 3986–3993.

    Article  PubMed  CAS  Google Scholar 

  58. Hiles I.D., Otsu M., Volinia S., et al. (1992) Phosphatidylinositol 3-kinase: structure and expression of the 110 kd catalytic subunit. Cell 70, 419–429.

    Article  PubMed  CAS  Google Scholar 

  59. Guo X.X., Huang Z., Bell M.W., et al. (2000) Tyrosine phosphorylation is involved in phosphatidylinositol 3-kinase activation in bovine rod outer segments. Mol. Vis. 6, 216–221.

    PubMed  CAS  Google Scholar 

  60. Waldbillig R.J., Fletcher R.T., Somers R.L., et al. (1988) IGF-1 receptors in the bovine neural retina: structure, kinase activity and comparison with retinal insulin receptors. Exp. Eye Res. 47, 587–607.

    Article  PubMed  CAS  Google Scholar 

  61. Zick Y., Spiegel A.M., and Sagi-Eisenberg R. (1987) Insulin-like growth factor 1 receptors in retinal rod outer segments. J. Biol. Chem. 262, 10,259–10,264.

    CAS  Google Scholar 

  62. Moran M.F., Koch C.A., Anderson D., et al. (1990) Src homology region 2 domains direct protein-protein interactions in signal transduction. Proc. Natl. Acad. Sci. USA 87, 8622–8626.

    Article  PubMed  CAS  Google Scholar 

  63. Waksman G., Shoelson S.E., Pant N., et al. (1993) Binding of a high affinity phosphotyrosyl peptide to the Src SH2 domain: crystal structures of the complexed and peptide-free forms. Cell 72, 779–790.

    Article  PubMed  CAS  Google Scholar 

  64. Ruderman N.B., Kapeller R., White M.F., et al. (1990) Activation of phosphatidylinositol 3-kinase by insulin. Proc. Natl. Acad. Sci. USA 87, 1411–1415.

    Article  PubMed  CAS  Google Scholar 

  65. Songyang Z., Shoelson S.E., Chaudhuri M., et al. (1993) SH2 domains recognize specific phosphopeptide sequences. Cell 72, 767–778.

    Article  PubMed  CAS  Google Scholar 

  66. Araki E., Lipes M.A., Patti M.E., et al. (1994) Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene. Nature 372, 186–190.

    Article  PubMed  CAS  Google Scholar 

  67. Tamemoto H., Kadowaki T., Tobe K., et al. (1994) Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1. Nature 372, 182–186.

    Article  PubMed  CAS  Google Scholar 

  68. McGinnis J.F., Matsumoto B., Whelan J.P., et al. (2002) Cytoskeleton participation in subcellular trafficking of signal transduction proteins in rod photoreceptor cells. J. Neurosci. Res. 67, 290–297.

    Article  PubMed  CAS  Google Scholar 

  69. Whelan J.P., McGinnis J.F. (1988) Light-dependent subcellular movement of photoreceptor proteins. J. Neurosci. Res. 20, 263–270.

    Article  PubMed  CAS  Google Scholar 

  70. Tabatabaie T., Waldon A.M., Jacob J.M., et al. (2000) COX-2 inhibition prevents insulin-dependent diabetes in low-dose streptozotocin-treated mice. Biochem. Biophys. Res. Commun. 273, 699–704.

    Article  PubMed  CAS  Google Scholar 

  71. Miyamoto Y., Sancar A. (1998) Vitamin B2-based blue-light photoreceptors in the retinohypothalamic tract as the photoactive pigments for setting the circadian clock in mammals. Proc. Natl. Acad. Sci. USA 95, 6097–6102.

    Article  PubMed  CAS  Google Scholar 

  72. Hao W. and Fong H.K. (1999) The endogenous chromophore of retinal G protein-coupled receptor opsin from the pigment epithelium. J. Biol. Chem. 274, 6085–6090.

    Article  PubMed  CAS  Google Scholar 

  73. Yu K.T., Werth D.K., Pastan I.H., et al. (1985) src kinase catalyzes the phosphorylation and activation of the insulin receptor kinase. J. Biol. Chem. 260, 5838–5846.

    PubMed  CAS  Google Scholar 

  74. Peterson J.E., Kulik G., Jelinek T., et al. (1996) Src phosphorylates the insulin-like growth factor type I receptor on the autophosphorylation sites. Requirement for transformation by src. J. Biol. Chem. 271, 31,562–31,571.

    CAS  Google Scholar 

  75. Ghalayini A.J., Desai N., Smith K.R., et al. (2002) Light-dependent association of Src with photoreceptor rod outer segment membrane proteins in vivo. J. Biol. Chem. 277, 1469–1476.

    Article  PubMed  CAS  Google Scholar 

  76. Saltiel A.R., Pessin J.E. (2002) Insulin signaling pathways in time and space. Trends Cell Biol. 12, 65–71.

    Article  PubMed  CAS  Google Scholar 

  77. Fain G.L., Matthews H.R., Cornwall M.C., et al. (2001) Adaptation in vertebrate photoreceptors. Physiol. Rev. 81, 117–151.

    PubMed  CAS  Google Scholar 

  78. Hollyfield J.G., Rayborn M.E. (1979) Photoreceptor outer segment development: light and dark regulate the rate of membrane addition and loss. Investig. Ophthalmol. Vis. Sci. 18, 117–132.

    CAS  Google Scholar 

  79. Basinger S., Hoffman R., and Matthes M. (1976) Photoreceptor shedding is initiated by light in the frog retina. Science 194, 1074–1076.

    Article  PubMed  CAS  Google Scholar 

  80. D’Mello S.R., Borodezt K., and Soltoff S.P. (1997) Insulin-like growth factor and potassium depolarization maintain neuronal survival by distinct pathways: possible involvement of PI 3-kinase in IGF-1 signaling. J. Neurosci. 17, 1548–1560.

    PubMed  CAS  Google Scholar 

  81. Spear N., Estevez A.G., Barbeito L., et al. (1997) Nerve growth factor protects PC12 cells against peroxynitrite-induced apoptosis via a mechanism dependent on phosphatidylinositol 3-kinase. J. Neurochem. 69, 53–59.

    Article  PubMed  CAS  Google Scholar 

  82. Noell W.K., Albrecht R. (1971) Irreversible effects on visible light on the retina: role of vitamin A. Science 172, 76–79.

    Article  PubMed  CAS  Google Scholar 

  83. Noell W.K. (1980) Possible mechanisms of photoreceptor damage by light in mammalian eyes. Vision Res. 20, 1163–1171.

    Article  PubMed  CAS  Google Scholar 

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  1. Departments of Cell Biology, Ophthalmology, and Biochemistry & Molecular Biology, University of Oklahoma Health Sciences Center; Dean A. McGee Eye Institute, 73104, Oklahoma City, OK

    Raju V. S. Rajala & Robert E. Anderson

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  1. Raju V. S. Rajala
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Rajala, R.V.S., Anderson, R.E. Light regulation of the insulin receptor in the retina. Mol Neurobiol 28, 123–138 (2003). https://doi.org/10.1385/MN:28:2:123

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