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The Phagocytosis of OS is Mediated by the PI3-Kinase Linked Tyrosine Kinase Receptor, Mer, and is Stimulated by Gas6

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Retinal Degenerations

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 533))

Abstract

The phagocytosis of the shed tips of photoreceptor outer segments (OS) by the cells of the adjacent retinal pigment epithelium (RPE) is vital to the survival of the photoreceptor (PR) cells (Young and Bok, 1969). If this phagocytosis is inhibited, death of the PRs occurs. This situation is observed in the Royal College of Surgeons (RCS) strain of rat (Bourne et al., 1938; Dowling and Sidman, 1962). In this animal model, a recessive mutation in the receptor tyrosine kinase (RTK) genemercauses the introduction of a stop codon early in the reading frame, with the result that functional Mer protein is never produced by the RPE cells (D’Cruz et al., 2000; Nandrot et al., 2000). This mutation affects the ability of the RPE cells to perform their normal function of phagocytosing the shed tips of the OS, resulting in degeneration of the underlying photoreceptor cells, and blindness (Bok and Hall, 1971; Mullen and LaVail, 1976; Edwards and Szamier, 1977).

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References

  • Akiyama, T., Ishida, J., Nakagawa, S., Ogawra, H., Watanabe, S., Itoh, N., Shibuya, M., and Fukami, Y., 1987, Genistein, a specific inhibitor of tyrosine-specific protein kinases, J.Biol. Chem.262:5592–5595.

    PubMed  CAS  Google Scholar 

  • Bok, D., and Hall, M. O., 1971, The role of the pigment epithelium in the etiology of inherited retinal degenerationJ. Cell Biol.49:664–682.

    Article  PubMed  CAS  Google Scholar 

  • Bourne, M. C., Campbell, D. A., and Tansley, K., 1938, Hereditary degeneration of the rat retinaBr. J. Ophthalmol.22:613–622.

    Article  PubMed  CAS  Google Scholar 

  • Chaitin, M. H., and Hall, M. O., 1983, Defective ingestion of rod outer segments by cultured dystrophic rat retinal pigment epithelium cellsInvest. Ophthalmol. Vis. Sci.24:812–820.

    PubMed  CAS  Google Scholar 

  • Chen, J., Carey, K., and Godowski, P. J., 1997, Identification of Gas6 as a ligand for Mer, a neural cell adhesion molecule related receptor tyrosine kinase implicated in cellular transformationOncogene14:2033–2039.

    Article  PubMed  CAS  Google Scholar 

  • D’Cruz, P. M., Yasumura, D., Weir, J., Matthes, M. T., Abderrahim, H., LaVail, M. M., and Vollrath, D., 2000, Mutation of the receptor tyrosine kinase gene Mertk in the retinal dystrophic ratHum. Mol. Gen.9:645–651.

    Google Scholar 

  • Dowling, J. E., and Sidman, R. L., 1962, Inherited retinal dystrophy in the ratJ. Cell Biol.14:73–109.

    Article  PubMed  CAS  Google Scholar 

  • Edwards, R. B., and Szamier, R. B., 1977, Defective phagocytosis of isolated rod outer segments by RCS rat pigment epithelium in cultureScience197:1001–1003.

    Article  PubMed  CAS  Google Scholar 

  • Feng, W., Yasamura, D., Matthes, M. T., LaVail, M. M., and Vollrath, D., 2002, Mertk triggers uptake of photoreceptor outer segments during phagocytosis by cultured retinal pigment epithelial cellsJ. Biol. Chem.277:17016–17022.

    Article  PubMed  CAS  Google Scholar 

  • Finneman, S. C., Bonilha, V. L., Marmorstein, A. D., and Rodriguez-Boulan, E., 1997, Phagocytosis of rod outer segments by retinal pigment epithelial cells requires coif, 5 integrin for binding but not for internalizationProc. Natl. Acad. Sci. USA. 94:12932–12937.

    Google Scholar 

  • Finneman, S.C., and Silverman, R. L., 2001, Differential roles of CD36 and avf35 integrin in photoreceptor phagocytosis by the retinal pigment epitheliumJ. Exp. Med. 194:1289–1298.

    Google Scholar 

  • Gal, A., Li, Y., Thompson, D. A., Weir, J., Orth, U., Jacobson, S. G., Apfelstedt-Sylla, D., and Vollrath, D., 2000, Mutations in Mertk, the human orthologue of the RCS rat retinal dystrophy gene cause retinitis pigmentosaNature Genetics26:270–271.

    Article  PubMed  CAS  Google Scholar 

  • Hall, M. O., and Abrams, T., 1987, Kinetic studies of rod outer segment binding and ingestion by cultured rat RPE cellsExp. Eye Res.45:907–922.

    Article  PubMed  CAS  Google Scholar 

  • Hall, M. O., Prieto, A. L., Obin, M. S., Abrams, T. A., Burgess, B. L., Heeb, M. J., and Agnew, B. J., 2001, Outer segment phagocytosis by cultured retinal pigment epithelial cells requires Gas6Exp. Eye Res.73:509–520.

    Article  PubMed  CAS  Google Scholar 

  • Hall, M. O., Obin, M. S., Prieto, A. L., Burgess, B. L., and Abrams, T. A., 2002, Gas6 binding to photoreceptor outer segments requires gamma-carboxyglutamic acid (Gla) and Cat*and is required for OS phagocytosis by RPE cells in vitroExp. Eye Res.75:391–400.

    PubMed  CAS  Google Scholar 

  • Huang, J., Nasr, M., Kim, Y., and Matthews, H. R., 1992, Genistein inhibits protein histidine kinaseJ. Biol Chem. 267:15511–15515.

    PubMed  CAS  Google Scholar 

  • LaVail, M. M., Sidman, R. L., and Gerhardt, C. O., 1975, Congenie strains of RCS rats with inherited retinal dystrophyJ. tiered.66:242–244.

    CAS  Google Scholar 

  • Manfioletti, G., Brancolini, C., Avanzi, G., and Schneider, C., 1993, The protein encoded by a growth arrest-specific gene (Gas6) is a new member of the vitamin K-dependent proteins related to protein S, a negative coregulator in the blood coagulation cascadeMol. Cell. Biol.13:4976–4985.

    PubMed  CAS  Google Scholar 

  • Mark, M. R., Chen, J., Hammonds, R. G., Sadick, M., and Godowski, P. J., 1996, Characterization of Gas6, a member of the superfamily of G-domain-containing proteins, as a ligand for Rse and Axl, JBiol. Chem. 271:9785–9789.

    Article  PubMed  CAS  Google Scholar 

  • Mayerson, P.L., Hall, M. O., Clark, V. M., and Abrams, T. A., 1985, An improved method for isolation and culture of retinal pigment epithelial cellsInvest. Ophthalmol. Vis. Sci. 26:1599–1609.

    PubMed  CAS  Google Scholar 

  • Mayerson, P. L., and Hall, M. O., 1986, Rat retinal pigment epithelial cells show specificity of phagocytosis in vitroJ. Cell Biol.103:299–308.

    Article  PubMed  CAS  Google Scholar 

  • Mullen, R. J., and LaVail, M. M., 1976, Inherited retinal dystrophy: primary defect in pigment epithelium determined with experimental rat chimerasScience192:799–801.

    Article  PubMed  CAS  Google Scholar 

  • Nagata, K., Ohashi, K., Nakano, T., Arita, H., Zong, C., Hanafusa, H., and Mizuno, K., 1996, Identification of the product of growth arrest-specific gene 6 as a common ligand for Axl, Sky and Mer receptor tyrosine kinase, J.Biol. Chem.271:30022–30027.

    Article  PubMed  CAS  Google Scholar 

  • Nandrot, E., Dufour, E. M., Provost, A. C., Pequignot, M. O., Bonnel, S., Gogat, K., Marchant, D., Rouillac, C., Sepulchre de Conde, B., Bihoreau, M-T., Shaver, C., Dufier, J-L., Marsac, C., Lathrop, M., Menasche, M., and Abitbol, M. M., 2000, Homozygous deletion in the coding sequence of the c-mer gene in the RCS rat unravels general mechanisms of physiological cell adhesion and apoptosisNeurobiol. Dis.7:586–599.

    Article  PubMed  CAS  Google Scholar 

  • Rameh, L.E., and Cantley, L.C., 1999, The role of phosphoinositide 3-kinase lipid products in cell functionJ. Biol. Chem. 274:8347–835.

    Google Scholar 

  • Thompson, D. A., McHenry, C. L., Li, Y., Richards, J. E., Othman, M. I., Schwinger, E., Vollrath, D., Jacobson, S. G., and Gal, A., 2002, Retinal dystrophy due to paternal isodisomy for chromosome 1 or chromosome 2, with homoallelism for mutations in RPE65 or Mertk, respectivelyAm. J. Hum. Genet.70:224–229.

    Article  PubMed  CAS  Google Scholar 

  • Vlahos, C. J., Matter, W. F., Hui, K. Y., and Brown, R. F., 1994, A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4- morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY 294002)J. Biol. Chem.269:52415248.

    Google Scholar 

  • Vollrath, D., Feng, W., Duncan, J. L., Yasamura, D., D’Cruz, P. M., Chappelow, A., Matthes, M. T., Kay, M. A., and LaVail, M. M., 2001, Correction of the retinal dystrophy phenotype of the RCS rat by viral gene transfer of MertkProc. Natl. Acad. Sci. U.S.A. 98:12584–12589.

    Google Scholar 

  • Wymann, M. P., and Pirola, L., 2000, Structure and function of phosphoinositide 3-kinasesBBA Lipids and Lipid Metabolism 1436:127–150.

    Google Scholar 

  • Yano, H., Nakanishi, S., Kimura, K., Hanai, N., Saitoh, Y., Fukui, Y., Nonomura, Y., and Matsuda, Y., 1993, Inhibition of histamine secretion by wortmannin through the blockade of phosphatidylinositol 3-kinase in RBL-2H3 cellsJ Biol. Chem.268:25846–25856.

    PubMed  CAS  Google Scholar 

  • Young, R. W., and Bok, D., 1969, Participation of the retinal pigment epithelium in the rod outer segment renewal processJ. Cell Biol.42:392–402.

    Article  PubMed  CAS  Google Scholar 

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Hall, M.O., Agnew, B.J., Abrams, T.A., Burgess, B.L. (2003). The Phagocytosis of OS is Mediated by the PI3-Kinase Linked Tyrosine Kinase Receptor, Mer, and is Stimulated by Gas6. In: LaVail, M.M., Hollyfield, J.G., Anderson, R.E. (eds) Retinal Degenerations. Advances in Experimental Medicine and Biology, vol 533. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-0067-4_41

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  • DOI: https://doi.org/10.1007/978-1-4615-0067-4_41

  • Publisher Name: Springer, Boston, MA

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