Abstract
MerTK is required for photoreceptor outer segment (POS) phagocytosis by retinal pigment epithelial (RPE) cells, a diurnal function essential for vision maintenance. In vivo, MerTK is stimulated at the time of the phagocytic peak through an intracellular signaling pathway. However, MerTK ligands Gas6 and Protein S are expressed in both RPE cells and photoreceptors, and at least one of them required for phagocytosis to occur. Still, their exact role in the retina was not clear until recently. This review combines results from different studies to shed the light on a tissue-specific regulation of MerTK function by its ligands. Indeed, with opposite effects on RPE phagocytosis and changes in their expression levels around the time of POS uptake, Gas6 and Protein S may contribute to the tight control of the acute phagocytic peak in the retina.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Anderson HA, Maylock CA, Williams JA et al (2003) Serum-derived protein S binds to phosphatidylserine and stimulates the phagocytosis of apoptotic cells. Nat Immunol 4(1):87–91
Burstyn-Cohen T, Heeb MJ, Lemke G (2009) Lack of protein S in mice causes embryonic lethal coagulopathy and vascular dysgenesis. J Clin Invest 119(10):2942–2953
Burstyn-Cohen T, Lew ED, Través PG et al (2012) Genetic dissection of TAM receptor-ligand interaction in retinal pigment epithelial cell phagocytosis. Neuron 76:1123–1132
D’Cruz PM, Yasumura D, Weir J et al (2000) Mutation of the receptor tyrosine kinase gene Mertk in the retinal dystrophic RCS rat. Hum Mol Genet 9:645–651
Dowling JE, Sidman RL (1962) Inherited retinal dystrophy in the rat. J Cell Biol 14:73–109
Fadok VA, Voelker DR, Campbell PA et al (1992) Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages. J Immunol 148(7):2207–2216
Feng W, Yasumura D, Matthes MT et al (2003) Mertk triggers uptake of photoreceptor outer segments during phagocytosis by cultured retinal pigment epithelial cells. J Biol Chem 277:17016–17022
Gal A, Li Y, Thompson DA et al (2000) Mutations in MERTK, the human orthologue of the RCS rat retinal dystrophy gene, cause retinitis pigmentosa. Nat Genet 26:270–271
Gallicchio M, Mitola S, Valdembri D et al (2005) Inhibition of vascular endothelial growth factor receptor 2-mediated endothelial cell activation by Axl tyrosine kinase receptor. Blood 105(5):1970–1976
Hafizi S, Dahlbäck B (2006a) Signalling and functional diversity within the Axl subfamily of receptor tyrosine kinases. Cytokine Growth Factor Rev 17(4):295–304
Hafizi S, Dahlbäck B (2006b) Gas6 and protein S. Vitamin K-dependent ligands for the Axl receptor tyrosine kinase subfamily. FEBS J 273(23):5231–5244
Hall MO, Prieto AL, Obin MS et al (2001) Outer segment phagocytosis by cultured retinal pigment epithelial cells requires Gas6. Exp Eye Res 73(4):509–520
Hall MO, Obin MS, Prieto AL et al (2002) Gas6 binding to photoreceptor outer segments requires gamma-carboxyglutamic acid (Gla) and Ca(2+) and is required for OS phagocytosis by RPE cells in vitro. Exp Eye Res 75(4):391–400
Hall MO, Obin MS, Heeb MJ et al (2005) Both protein S and Gas6 stimulate outer segment phagocytosis by cultured rat retinal pigment epithelial cells. Exp Eye Res 81:581–591
Hanayama R, Tanaka M, Miwa K et al (2002) Identification of a factor that links apoptotic cells to phagocytes. Nature 417(6885):182–187
LaVail MM (1976) Rod outer segment disk shedding in rat retina: relationship to cyclic lighting. Science 194:1071–1074
Lemke G (2013) Biology of the TAM receptors. Cold Spring Harb Perspect Biol 5(11):a009076
Law AL, Parinot C, Chatagnon J et al (2015) Cleavage of Mer tyrosine kinase (MerTK) from the cell surface contributes to the regulation of retinal phagocytosis. J Biol Chem 290(8):4941–4952
Lew ED, Oh J, Burrola PG et al (2014) Differential TAM receptor-ligand-phospholipid interactions delimit differential TAM bioactivities. elife 3:e03385
Liao D, Wang X, Li M et al (2009) Human protein S inhibits the uptake of AcLDL and expression of SR-A through Mer receptor tyrosine kinase in human macrophages. Blood 113(1):165–174
McCloskey P, Fridell YW, Attar E et al (1997) GAS6 mediates adhesion of cells expressing the receptor tyrosine kinase Axl. J Biol Chem 272:23285–23291
Melaragno MG, Cavet ME, Yan C et al (2004) Gas6 inhibits apoptosis in vascular smooth muscle: role of Axl kinase and Akt. J Mol Cell Cardiol 37:881–887
Nakano T, Ishimoto Y, Kishino J et al (1997) Cell adhesion to phosphatidylserine mediated by a product of growth arrest-specific gene 6. J Biol Chem 272(47):29411–29414
Nandrot E, Dufour EM, Provost AC et al (2000) Homozygous deletion in the coding sequence of the c-mer gene in RCS rats unravels general mechanisms of physiological cell adhesion and apoptosis. Neurobiol Dis 7:586–599
Nandrot EF, Kim Y, Brodie SE et al (2004) Loss of synchronized retinal phagocytosis and age-related blindness in mice lacking alphavbeta5 integrin. J Exp Med 200:1539–1545
Nandrot EF, Anand M, Almeida D et al (2007) Essential role for MFG-E8 as ligand for alphavbeta5 integrin in diurnal retinal phagocytosis. Proc Natl Acad Sci U S A 104:12005–12010
Parinot C, Chatagnon J, Roux S et al (in revision) Gas6 and Protein S ligands cooperate to regulate MerTK rhythmic activity required for circadian retinal phagocytosis
Prasad D, Rothlin CV, Burrola P et al (2006) TAM receptor function in the retinal pigment epithelium. Mol Cell Neurosci 33(1):96–108
Ruggiero L, Connor MP, Chen J et al (2012) Diurnal, localized exposure of phosphatidylserine by rod outer segment tips in wild-type but not Itgb5−/− or Mfge8−/− mouse retina. Proc Natl Acad Sci U S A 109(21):8145–8148
Ryeom SW, Silverstein RL, Scotto A et al (1996) Binding of anionic phospholipids to retinal pigment epithelium may be mediated by the scavenger receptor CD36. J Biol Chem 271(34):20536–20539
Scott RS, McMahon EJ, Pop SM et al (2001) Phagocytosis and clearance of apoptotic cells is mediated by MER. Nature 411:207–211
Stenhoff J, Dahlback B, Hafizi S (2004) Vitamin K-dependent Gas6 activates ERK kinase and stimulates growth of cardiac fibroblasts. Biochem Biophys Res Commun 319:871–878
Stitt TN, Conn G, Goret M et al (1995) The anticoagulation factor protein S and its relative, Gas6, are ligands for the Tyro 3/Axl family of receptor tyrosine kinases. Cell 80(4):661–670
Strauss O (2005) The retinal pigment epithelium in visual function. Physiol Rev 85(3):845–881
Tschernutter M, Jenkins SA, Waseem NH et al (2006) Clinical characterisation of a family with retinal dystrophy caused by mutation in the Mertk gene. Br J Ophthalmol 90:718–723
Uehara H, Shacter E (2008) Auto-oxidation and oligomerization of protein S on the apoptotic cell surface is required for Mer tyrosine kinase-mediated phagocytosis of apoptotic cells. J Immunol 180(4):2522–2530
Varnum BC, Young C, Elliott G et al. (1995) Axl receptor tyrosine kinase stimulated by the vitamin K-dependent protein encoded by growth-arrest-specific gene 6. Nature 373(6515):623–626
Walker FJ (1980) Regulation of activated protein C by a new protein. A possible function for bovine Protein S. J Biol Chem 255(12):5521–5524
Young RW, Bok D (1969) Participation of the retinal pigment epithelium in the rod outer segment renewal process. J Cell Biol 42:392–403
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2018 Springer International Publishing AG, part of Springer Nature
About this paper
Cite this paper
Nandrot, E.F. (2018). Opposite Roles of MerTK Ligands Gas6 and Protein S During Retinal Phagocytosis. In: Ash, J., Anderson, R., LaVail, M., Bowes Rickman, C., Hollyfield, J., Grimm, C. (eds) Retinal Degenerative Diseases. Advances in Experimental Medicine and Biology, vol 1074. Springer, Cham. https://doi.org/10.1007/978-3-319-75402-4_70
Download citation
DOI: https://doi.org/10.1007/978-3-319-75402-4_70
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-75401-7
Online ISBN: 978-3-319-75402-4
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)