Insensitivity of PI3K/Akt/GSK3 signaling in peripheral blood mononuclear cells of age-related macular degeneration patients

Abstract

Our recent studies with cultured retinal pigment epithelium cells suggested that overexpression of interleukin 17 receptor C (IL-17RC), a phenomenon observed in peripheral blood and chorioretinal tissues with age-related macular degeneration (AMD), was associated with altered activation of phosphatidylinositide 3-kinase (PI3K), Akt, and glycogen synthase kinase 3 (GSK3). We wondered whether or not altered PI3K, Akt, and GSK3 activities could be detected in peripheral blood mononuclear cells (PBMC) obtained from AMD patients. In the patients' PBMC, absent or reduced serine-phosphorylation of GSK3α or GSK3β was observed, which was accompanied with increased phosphorylation of GSK3 substrates (e.g. CCAAT enhancer binding protein α, insulin receptor substrate 1, and TAU), indicative of enhanced GSK3 activation. In addition, decreased protein mass of PI3K85α and tyrosine-phosphorylation of PI3K50α was present in PBMC of the AMD patients, suggesting impaired PI3K activation. Moreover, abnormally lowered molecular weight forms of Akt and GSK3 were detected in PBMC of the AMD patients. These data demonstrate that despite the presence of high levels of IL-17RC, Wnt-3a and vascular endothelial growth factor, the PI3K/Akt/GSK3 signaling pathway is insensitive to these stimuli in PBMC of the AMD patients. Thus, measurement of PI3K/Akt/GSK3 expression and activity in PBMC may serve as a surrogate biomarker for AMD.

Keywords

phosphatidylinositide 3-kinase (PI3K) / protein kinase B (PKB or Akt) / glycogen synthase kinase 3 (GSK3) / age-related macular degeneration (AMD) / peripheral blood mononuclear cells (PBMC)

References

[1] Wang H, Han  X, Wittchen ES , TNF-α mediates choroidal neovascularization by upregulating VEGF expression in RPE through ROS-dependent β-catenin activation[J]. Mol Vis, 2016, 22: 116–128

[2] Bhutto I, Lutty  G. Understanding age-related macular degeneration (AMD): relationships between the photoreceptor/retinal pigment epithelium/Bruch's membrane/choriocapillaris complex[J]. Mol Aspects Med, 2012, 33(4): 295–317

[3] Morohoshi K, Goodwin  AM, Ohbayashi M , Autoimmunity in retinal degeneration: autoimmune retinopathy and age-related macular degeneration[J]. J Autoimmun, 2009, 33(3-4): 247–254

[4] Janeway CA Jr ,  Travers P ,  Walport M ,  The complement system and innate immunity. In: Charles A Janeway, Jr, Paul Travers, Mark Walport, et al., Editors. Immunobiology: The Immune System in Health and Disease, 5th edition[M].New York: Garland Science. 2001.

[5] Zipfel PF, Lauer  N, Skerka C . The role of complement in AMD[J]. Adv Exp Med Biol, 2010, 703: 9–24

[6] Wei L, Liu  B, Tuo J , Hypomethylation of the IL17RC promoter associates with age-related macular degeneration[J]. Cell Rep, 2012, 2(5): 1151–1158

[7] Oliver VF, Franchina  M, Jaffe AE , Hypomethylation of the IL17RC promoter in peripheral blood leukocytes is not a hallmark of age-related macular degeneration[J]. Cell Rep, 2013, 5(6): 1527–1535

[8] Liu X. Overstimulation can create health problems due to increases in PI3K/Akt/GSK3 insensitivity and GSK3 activity[J]. Springerplus, 2014, 3: 356

[9] Zhou T, Hu  Y, Chen Y , The pathogenic role of the canonical Wnt pathway in age-related macular degeneration[J]. Invest Ophthalmol Vis Sci, 2010, 51(9): 4371–4379

[10] Jope RS, Johnson  GV. The glamour and gloom of glycogen synthase kinase-3[J]. Trends Biochem Sci, 2004, 29(2): 95–102

[11] Watcharasit P, Bijur  GN, Zmijewski JW , Direct, activating interaction between glycogen synthase kinase-3beta and p53 after DNA damage[J]. Proc Natl Acad Sci U S A, 2002, 99(12): 7951–7955

[12] Grimes CA, Jope  RS. CREB DNA binding activity is inhibited by glycogen synthase kinase-3 beta and facilitated by lithium[J]. J Neurochem, 2001, 78(6): 1219–1232

[13] Carpenter CL, Duckworth  BC, Auger KR , Purification and characterization of phosphoinositide 3-kinase from rat liver[J]. J Biol Chem, 1990, 265(32): 19704–19711

[14] Liu X, Lu  X, Song K , Natural functions of PLIN2 mediating Wnt/LiCl signaling and GSK3/GSK3 substrates-related effects are modulated by lipid[J]. Mol Cell Biol, 2015(3), 36: 421–437

[15] Liu X, Yao  Z. Chronic over-nutrition and dysregulation of GSK3 in diseases[J]. Nutr Metab (Lond), 2016, 13: 49

[16] Cooke Bailey JN ,  Hoffman JD ,  Sardell RJ , The application of genetic risk scores in age-related macular degeneration: a review[J]. J Clin Med, 2016, 5(3): 31

[17] Gemenetzi M, Lotery  AJ. Complement pathway biomarkers and age-related macular degeneration[J]. Eye (Lond), 2016, 30(1): 1–14

[18] Wang Y, Wang  VM, Chan CC . The role of anti-inflammatory agents in age-related macular degeneration (AMD) treatment[J]. Eye (Lond), 2011, 25(2): 127–139

[19] Fisher DE, Jonasson  F, Eiriksdottir G , Age-related macular degeneration and mortality in community-dwelling elders: the age, gene/environment susceptibility Reykjavik study[J]. Ophthalmology, 2015, 122(2): 382–390

[20] Topouzis F, Anastasopoulos  E, Augood C , Association of diabetes with age-related macular degeneration in the EUREYE study[J]. Br J Ophthalmol, 2009, 93(8): 1037–1041

[21] Fernandez AB, Panza  GA, Cramer B , Age-related macular degeneration and incident stroke: a systematic review and meta-analysis[J]. PLoS One, 2015, 10(11): e0142968

[22] Moore SF, van den Bosch  MT, Hunter RW , Dual regulation of glycogen synthase kinase 3 (GSK3)α/β by protein kinase C (PKC)α and Akt promotes thrombin-mediated integrin αIIbβ3 activation and granule secretion in platelets[J]. J Biol Chem, 2013, 288(6): 3918–3928

[23] Li DW, Liu  ZQ, Chen W , Association of glycogen synthase kinase-3β with Parkinson's disease (review)[J]. Mol Med Rep, 2014, 9(6): 2043–2050

[24] Rakoff-Nahoum S. Why cancer and inflammation[J]? Yale J Biol Med, 2006, 79(3-4): 123–130

[25] Jope RS, Yuskaitis  CJ, Beurel E . Glycogen synthase kinase-3 (GSK3): inflammation, diseases, and therapeutics[J]. Neurochem Res, 2007, 32(4-5): 577–595

[26] Draznin B. Molecular mechanisms of insulin resistance: serine phosphorylation of insulin receptor substrate-1 and increased expression of p85alpha: the two sides of a coin[J]. Diabetes, 2006, 55(8): 2392–2397

[27] Yu Y, Run  X, Liang Z , Developmental regulation of tau phosphorylation, tau kinases, and tau phosphatases[J]. J Neurochem, 2009, 108(6): 1480–1494

Acknowledgements

This study was supported by intramural research funding of National Center for Complementary and Alternative Medicine (now is National Center for Complementary and Integrative Health), NIH, the US Department of Health and Human Services (to X.L.) and an operating grant (MOP 123279) from Canadian Institutes for Health Research (to Z.Y.).

RIGHTS & PERMISSIONS

2017 2017 by the Journal of Biomedical Research. All rights reserved