Advertisement

Protein Serine/Threonine Phosphatases-1 and -2A in Lens Development and Pathogenesis

  • Wen-Feng Hu
  • Xiao-Hui Hu
  • Weike Ji
  • Zhao-Xia Huang
  • Ling Wang
  • Zachary Woodward
  • Quan Dong Nguyen
  • David Wan-Cheng Li
Chapter
Part of the Oxidative Stress in Applied Basic Research and Clinical Practice book series (OXISTRESS)

Abstract

The protein serine/threonine phosphatases are major cellular phosphatases, responsible for 98 % dephosphorylation of proteins in eukaryotes. In the ocular lens, they are highly expressed and play important roles in both development and pathogenesis. In the present review, we have summarized these two aspects, which provide a basis for further studies on these important signaling molecules in the eye.

Keywords

Phosphatases Dephosphorylation Lens Apoptosis Cell differentiation 

Notes

Acknowledgments

This work was supported in part by the National Institutes of Health grants [EY015765 and EY018380], the Cooperative Innovation Center of Engineering and New Products for Developmental Biology of Hunan Province (20134486), the National Natural Science Foundation of China (81272228), and the Lotus Scholar Program, and the Chinese Scholarship Council (WKJ, XHH, WFH).

References

  1. 1.
    Hunter T. Protein kinases and phosphatases: the yin and yang of protein phosphorylation and signaling. Cell. 1995;80:225–36.PubMedCrossRefGoogle Scholar
  2. 2.
    Gallego M, Virshup DM. Protein serine/threonine phosphatases: life, death, and sleeping. Curr Opin Cell Biol. 2005;17:197–202.PubMedCrossRefGoogle Scholar
  3. 3.
    Moorhead GBG, Trinkle-Mulcahy L, Ulke-Lemée A. Emerging roles of nuclear protein phosphatases. Nat Rev Mol Cell Biol. 2007;8:234–44.PubMedCrossRefGoogle Scholar
  4. 4.
    Mumby MC, Walter G. Protein serine/threonine phosphatases: structure, regulation, and functions in cell growth. Physiol Rev. 1993;73:673–99.PubMedGoogle Scholar
  5. 5.
    Xu Y, Xing Y, Chen Y, Chao Y, Lin Z, Fan E, Yu JW, Strack S, Jeffrey PD, Shi Y. Structure of the protein phosphatase 2A holoenzyme. Cell. 2006;127:1239–51.PubMedCrossRefGoogle Scholar
  6. 6.
    Yan Q, Mao Y-W, Li DW. Protein serine/threonine phosphatases in the nervous system. Encycl Neurosci. 2009;4:3325–9.CrossRefGoogle Scholar
  7. 7.
    Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M. Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell. 2006;127:635–48.PubMedCrossRefGoogle Scholar
  8. 8.
    Brewis ND, Street AJ, Prescott AR, Cohen PT. PPX, a novel protein serine/threonine phosphatase localized to centrosomes. EMBO J. 1993;12:987–96.PubMedCentralPubMedGoogle Scholar
  9. 9.
    Chen MX, McPartlin AE, Brown L, Chen YH, Barker HM, Cohen PT. A novel human protein serine/threonine phosphatase, which possesses four tetratricopeptide repeat motifs and localizes to the nucleus. EMBO J. 1994;13:4278–90.PubMedCentralPubMedGoogle Scholar
  10. 10.
    Bastians H, Ponstingl H. The novel human protein serine/threonine phosphatase 6 is a functional homologue of budding yeast Sit4p and fission yeast pp e1, which are involved in cell cycle regulation. J Cell Sci. 1996;109:2865–74.PubMedGoogle Scholar
  11. 11.
    Huang X, Honkanen RE. Molecular cloning, expression, and characterization of a novel human serine/threonine protein phosphatase, PP7, that is homologous to Drosophila retinal degeneration C gene product (rdgC). J Biol Chem. 1998;273:1462–8.PubMedCrossRefGoogle Scholar
  12. 12.
    McAvoy JW. Induction of the eye lens. Differentiation. 1980;17:137–49.PubMedCrossRefGoogle Scholar
  13. 13.
    Piatigorsky J. Lens differentiation in vertebrates. A review of cellular and molecular features. Differentiation. 1981;19:134–53.PubMedCrossRefGoogle Scholar
  14. 14.
    Grainger RM. Embryonic lens induction: shedding light on vertebrate tissue determination. Trends Genet. 1992;8:349–55.PubMedCrossRefGoogle Scholar
  15. 15.
    Wride MA. Cellular and molecular features of lens differentiation: a review of recent advances. Differentiation. 1996;61:77–93.PubMedCrossRefGoogle Scholar
  16. 16.
    O’Rahilly R. The early development of the eye in staged human embryos. Contrib Embryol Carnegie Inst. 1966;38:1–42.Google Scholar
  17. 17.
    Kuwabara T, Imaizumi M. Denucleation process of the lens. Invest Ophthalmol Vis Sci. 1974;13:973–81.Google Scholar
  18. 18.
    Sanwal M, Muel AS, Chaudun E, Courtois Y, Counis MF. Chromatin condensation and terminal differentiation process in embryonic chicken lens in vivo and in vitro. Exp Cell Res. 1986;167:429–39.PubMedCrossRefGoogle Scholar
  19. 19.
    McAvoy JW, Chamberlain CG. Growth factors in the lens. Prog Growth Factor Res. 1990;2:29–43.PubMedCrossRefGoogle Scholar
  20. 20.
    Lang RA. Which factors stimulate lens fiber cell differentiation in vivo? Invest Ophthalmol Vis Sci. 1999;40:3075–8.PubMedGoogle Scholar
  21. 21.
    Chow RL. Early eye development in vertebrates. Annu Rev Cell Dev Biol. 2001;17:255–96.PubMedCrossRefGoogle Scholar
  22. 22.
    Liu WB, Li Y, Zhang L, Chen HG, Sun S, Liu JP, Liu Y, Li DW. Differential expression of the catalytic subunits for PP-1 and PP-2A and the regulatory subunits for PP-2A in mouse eye. Mol Vis. 2008;14:762–73.PubMedCentralPubMedGoogle Scholar
  23. 23.
    Li DW-C, Xiang H, Fass U, Zhang X-Y. Analysis of expression patterns of protein phosphatase-1 and phosphatase-2A in rat and bovine lenses. Invest Ophthalmol Vis Sci. 2001;42:2603–9.PubMedGoogle Scholar
  24. 24.
    Liu WB, Yan Q, Liu FY, Tang XC, Chen HG, Liu J, Nie L, Zhang XW, Ji WK, Hu XH, Hu WF, Woodward Z, Wu KL, Wu MX, Liu XL, Luo LX, Yu MB, Liu YZ, Liu SJ, Li DW. Protein serine/threonine phosphotase-1 is essential in governing normal development of vertebrate eye. Curr Mol Med. 2012;12:1361–71.PubMedCrossRefGoogle Scholar
  25. 25.
    Yan Q, Liu WB, Qin J, Liu J, Chen HG, Huang X, Chen L, Sun S, Deng M, Gong L, Li Y, Zhang L, Liu Y, Feng H, Xiao Y, Liu Y, Li DW. Protein phosphatase-1 dephosphorylates Pax-6, a transcription factor controlling brain and eye development. J Biol Chem. 2007;282(19):13954–65.PubMedCrossRefGoogle Scholar
  26. 26.
    Ludlow JW, Glendening CL, Livingston DM, DeCarprio JA. Specific enzymatic dephosphorylation of the retinoblastoma protein. Mol Cell Biol. 1993;13:367–72.PubMedCentralPubMedGoogle Scholar
  27. 27.
    Xiao L, Gong LL, Yuan D, Deng M, Zeng XM, Chen LL, Zhang L, Yan Q, Liu JP, Hu XH, Sun SM, Liu J, Ma HL, Zheng CB, Fu H, Chen PC, Zhao JQ, Xie SS, Zou LJ, Xiao YM, Liu WB, Zhang J, Liu Y, Li DW. Protein phosphatase-1 regulates Akt1 signal transduction pathway to control gene expression, cell survival and differentiation. Cell Death Differ. 2010;17(9):1448–62.PubMedCrossRefGoogle Scholar
  28. 28.
    Li DW, Fass U, Huizar I, Spector A. Okaidac acid-induced lens epithelial cell apoptosis requires inhibition of phosphatase-1 and is associated with induction of gene expression including p53 and bax. Eur J Biochem. 1998;257:351–61.PubMedCrossRefGoogle Scholar
  29. 29.
    Li DW, Liu JP, Schmid PC, Schlosser R, Feng H, Liu WB, Yan Q, Gong L, Sun SM, Deng M, Liu Y. Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities. Oncogene. 2006;25:3006–22.PubMedCrossRefGoogle Scholar
  30. 30.
    Yan Q, Liu J-P, Li DW-C. Apoptosis in the ocular lens: role in development and pathogenesis. Differentiation. 2006;74:195–211.PubMedCrossRefGoogle Scholar
  31. 31.
    Zhang L, Yan Q, Liu JP, Zou LJ, Liu J, Sun S, Deng M, Gong L, Ji WK, Li DW. Apoptosis: its functions and control in the ocular lens. Curr Mol Med. 2010;10(9):864–75.PubMedCrossRefGoogle Scholar
  32. 32.
    Hu WF, Gong L, Cao Z, Ma H, Ji W, Deng M, Liu M, Hu XH, Chen P, Yan Q, Chen HG, Liu J, Sun S, Zhang L, Liu JP, Wawrousek E, Li DW. αA- and αB-crystallins interact with caspase-3 and Bax to guard mouse lens development. Curr Mol Med. 2012;12(2):177–87.PubMedCrossRefGoogle Scholar
  33. 33.
    Glucksmann A. Cell deaths in normal vertebrate ontogeny. Biol Rev. 1951;26:59–86.PubMedCrossRefGoogle Scholar
  34. 34.
    Silver J, Hughes AFW. The role of cell death during morphogenesis of the mammalian eye. J Morphol. 1973;140:159–70.PubMedCrossRefGoogle Scholar
  35. 35.
    Ishizaki Y, Voyvodic JT, Burne JF, Raff MC. Control of lens epithelial cell survival. J Cell Biol. 1993;121:899–908.PubMedCrossRefGoogle Scholar
  36. 36.
    Ozeki H, Ogura Y, Hirabayashi Y, Shimada S. Suppression of lens stalk cell apoptosis by hyaluronic acid leads to faulty separation of the lens vesicle. Exp Eye Res. 2001;72:63–70.PubMedCrossRefGoogle Scholar
  37. 37.
    Bozanic D, Tafra R, Saraga-Babic M. Role of apoptosis and mitosis during human eye development. Eur J Cell Biol. 2003;82:421–9.PubMedCrossRefGoogle Scholar
  38. 38.
    Mohamed YH, Amemiya T. Apoptosis and lens vesicle development. Eur J Ophthalmol. 2003;13(1):1–10.PubMedGoogle Scholar
  39. 39.
    Hettmann T, Barton K, Leiden JM. Microphthalmia due to p53-mediated apoptosis of anterior lens epithelial cells in mice lacking the CREB-2 transcription factor. Dev Biol. 2000;222:110–23.PubMedCrossRefGoogle Scholar
  40. 40.
    Blixt A, Mahlapuu M, Aitola M, Pelto-Huikko M, EneRback S, Carlsson P. A forkhead gene, FoxE3, is essential for lens epithelial proliferation and closure of the lens vesicle. Genes Dev. 2000;14:245–54.PubMedCentralPubMedGoogle Scholar
  41. 41.
    Fromm L, Shawlot W, Gunning K, Butel JS, OveRbeek PA. The retinoblastoma protein-binding region of simian virus 40 large T antigen alters cell cycle regulation in lenses of transgenic mice. Mol Cell Biol. 1994;14:6743–54.PubMedCentralPubMedGoogle Scholar
  42. 42.
    Pan H, Griep AE. Temporally distinct patterns of p53-dependent and p53-independent apoptosis during mouse lens development. Genes Dev. 1995;9:2157–69.PubMedCrossRefGoogle Scholar
  43. 43.
    Morgenbesser SD, Schreiber-Agus N, Bidder M, Mahon KA, OveRbeek PA, Horner J, DePinho RA. Contrasting roles for c-Myc and L-Myc in the regulation of cellular growth and differentiation in vivo. EMBO J. 1995;14:743–56.PubMedCentralPubMedGoogle Scholar
  44. 44.
    Nakamura T, Pichel JG, Williams-Simons L, Westphal H. An apoptotic defect in lens differentiation caused by human p53 is rescued by a mutant allele. Proc Natl Acad Sci U S A. 1995;92:6142–6.PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Robinson ML, MacMillan-Crow LA, Thompson JA, OveRbeek PA. Expression of a truncated FGF receptor results in defective lens development in transgenic mice. Development. 1996;121:3959–67.Google Scholar
  46. 46.
    Gomez Lahoz E, Liegeois NJ, Zhang P, Engelman JA, Horner J, Silverman A, Burde R, Roussel MF, Sherr CJ, Elledge SJ, DePinho RA. Cyclin D- and E-dependent kinases and the p57(KIP2) inhibitor: cooperative interactions in vivo. Mol Cell Biol. 1997;19:353–63.Google Scholar
  47. 47.
    McCaffrey J, Yamasaki L, Dyson NJ, Harlow E, Griep AE. Disruption of retinoblastoma protein family function by human papillomavirus type 16 E7 oncoprotein inhibits lens development in part through E2F-1. Mol Cell Biol. 1999;19:6458–68.PubMedCentralPubMedGoogle Scholar
  48. 48.
    de Iongh RU, Lovicu FJ, Overbeek PA, Schneider MD, Joya J, Hardeman ED, McAvoy JW. Requirement for TGFbeta receptor signaling during terminal lens fiber differentiation. Development. 2001;128:3995–4010.PubMedGoogle Scholar
  49. 49.
    Li WC, Kuszak JR, Dunn K, Wang RR, Ma W, Wang GM, Spector A, et al. Lens epithelial cell apoptosis appears to be a common cellular basis for non-congenital cataract development in humans and animals. J Cell Biol. 1995;130:169–81.PubMedCrossRefGoogle Scholar
  50. 50.
    Li W-C, Kuszak JR, Wang G-M, Wu Z-Q, Spector A. Calcimycin-induced lens epithelial cell apoptosis contributes to cataract formation. Exp Eye Res. 1995;61:89–96.Google Scholar
  51. 51.
    Li W-C, Spector A. Lens epithelial cell apoptosis is an early event in the development of UVB-induced cataract. Free Radic Biol Med. 1996;20:301–11.PubMedCrossRefGoogle Scholar
  52. 52.
    Zhou J, Leonard M, Van Bockstaele E, Menko AS. Mechanism of Src kinase induction of cortical cataract following exposure to stress: destabilization of cell-cell junctions. Mol Vis. 2007;13:1298–310.PubMedGoogle Scholar
  53. 53.
    Michael R, Vrensen GF, van Marle J, Gan L, SodeRberg PG. Apoptosis in the rat lens after in vivo threshold dose ultraviolet irradiation. Invest Ophthalmol Vis Sci. 1998;39:2681–7.PubMedGoogle Scholar
  54. 54.
    Michael R, Vrensen GF, van Marle J, Lofgren S, Soderberg PG. Repair in the rat lens after threshold ultraviolet radiation injury. Invest Ophthalmol Vis Sci. 2000;41:204–12.PubMedGoogle Scholar
  55. 55.
    Ayala M, Strid H, Jacobsson U, Söderberg PG. p53 Expression and apoptosis in the lens after ultraviolet radiation exposure. Invest Ophthalmol Vis Sci. 2007;48(9):4187–91.PubMedCrossRefGoogle Scholar
  56. 56.
    Takamura Y, Kubo E, Tsuzuki S, Akagi Y. Apoptotic cell death in the lens epithelium of rat sugar cataract. Exp Eye Res. 2003;77:51–7.PubMedCrossRefGoogle Scholar
  57. 57.
    Murata M, Ohta N, Sakurai S, Alam S, Tsai J, Kador PF, Sato S. The role of aldose reductase in sugar cataract formation: aldose reductase plays a key role in lens epithelial cell death (apoptosis). Chem Biol Interact. 2001;130–132(1–3):617–25.PubMedCrossRefGoogle Scholar
  58. 58.
    Tamada Y, Fukiage C, Nakamura Y, Azuma M, Kim YH, Shearer TR. Evidence for apoptosis in the selenite rat model of cataract. Biochem Biophys Res Commun. 2000;275:300–6.PubMedCrossRefGoogle Scholar
  59. 59.
    Yoshizawa K, Oishi Y, Nambu H, Yamamoto D, Yang J, Senzaki H, Miki H, Tsubura A. Cataractogenesis in neonatal Sprague-Dawley rats by N-methyl-N-nitrosourea. Toxicol Pathol. 2000;28:555–64.PubMedCrossRefGoogle Scholar
  60. 60.
    Wolf N, Penn P, Pendergrass W, Van Remmen H, Bartke A, Rabinovitch P, Martin GM. Age-related cataract progression in five mouse models for anti-oxidant protection or hormonal influence. Exp Eye Res. 2005;81:276–85.PubMedCrossRefGoogle Scholar
  61. 61.
    Nishi O, Nishi K. Apoptosis in lens epithelial cells of human cataracts. J Eye. 1998;15:1309–13 (In Japanese).Google Scholar
  62. 62.
    Takamura Y, Sugimoto Y, Kubo E, Takahashi Y, Akagi Y. Immunohistochemical study of apoptosis of lens epithelial cells in human and diabetic rat cataracts. Jpn J Ophthalmol. 2001;45:559–63.PubMedCrossRefGoogle Scholar
  63. 63.
    Okamura N, Ito Y, Shibata MA, Ikeda T, Otsuki Y. Fas-mediated apoptosis in human lens epithelial cells of cataracts associated with diabetic retinopathy. Med Electron Microsc. 2002;35:234–41.PubMedCrossRefGoogle Scholar
  64. 64.
    Charakidas A, Kalogeraki A, Tsilimbaris M, Koukoulomatis P, Brouzas D, Delides G. Lens epithelial apoptosis and cell proliferation in human age-related cortical cataract. Eur J Ophthalmol. 2005;15(2):213–20.PubMedGoogle Scholar
  65. 65.
    Harocopos GJ, Alvares KM, Kolker AE, Beebe DC. Human age-related cataract and lens epithelial cell death. Invest Ophthalmol Vis Sci. 1998;39:2696–706.PubMedGoogle Scholar
  66. 66.
    Mihara E, Miyata H, Nagata M, Ohama E. Lens epithelial cell damage and apoptosis in atopic cataract-histopathological and immunohistochemical studies. Jpn J Ophthalmol. 2000;44:695–6.PubMedCrossRefGoogle Scholar
  67. 67.
    Lee EH, Wan XH, Song J, Kang JJ, Cho JW, Seo KY, Lee JH. Lens epithelial cell death and reduction of anti-apoptotic protein Bcl-2 in human anterior polar cataracts. Mol Vis. 2002;11:235–40.Google Scholar
  68. 68.
    Mulhern ML, Madson CJ, Danford A, Ikesugi K, Kador PF, Shinohara T. The unfolded protein response in lens epithelial cells from galactosemic rat lenses. Invest Ophthalmol Vis Sci. 2006;47(9):3951–9.PubMedCrossRefGoogle Scholar
  69. 69.
    Liu WB, Hu XH, Zhang XW, Deng MX, Nie L, Hui SS, Duan W, Tao M, Zhang C, Liu J, Hu WF, Huang ZX, Li L, Yi M, Li TT, Wang L, Liu Y, Liu SJ, Li DW. Protein serine/threonine phosphotase-2A are differentially expressed and regulates eye development in vertebrates. Curr Mol Med. 2013;13(8):1376–84.PubMedCrossRefGoogle Scholar
  70. 70.
    Wassarman DA, Solomon NM, Chang HC, Karim FD, Therrien M, Rubin GM. Protein phosphatase 2A positively and negatively regulates Ras1-mediated photoreceptor development in Drosophila. Genes Dev. 1996;10:272–8.PubMedCrossRefGoogle Scholar
  71. 71.
    Edwards SC, O’Day PM, Herrera DC. Characterization of protein phosphatases type 1 and type 2A in Limulus nervous tissue: their light regulation in the lateral eye and evidence of involvement in the photoresponse. Vis Neurosci. 1996;13:73–85.PubMedCrossRefGoogle Scholar
  72. 72.
    Rorick AM, Mei W, Liette NL, Phiel C, El-Hodiri HM, Yang J. PP2A:B56epsilon is required for eye induction and eye field separation. Dev Biol. 2007;302:477–93.PubMedCrossRefGoogle Scholar
  73. 73.
    Qin J, Chen HG, Yan Q, Deng M, Liu J, Doerge S, Ma W, Dong Z, Li DW. Protein phosphatase-2a is a target of epigallocatechin-3-gallate and modulates p53-Bak apoptotic pathway. Cancer Res. 2008;68:4150–62.PubMedCrossRefGoogle Scholar
  74. 74.
    Kantorow M, Kays T, Horwitz J, Huang Q, Sun J, Piatigorsky J, Carper D. Differential display detects altered gene expression between cataractous and normal human lenses. Invest Ophthalmol Vis Sci. 1998;39:2344–54.PubMedGoogle Scholar
  75. 75.
    Liu J, Ji W, Sun S, Zhang L, Chen HG, Mao Y, Liu L, Zhang X, Gong L, Deng M, Chen L, Han WJ, Chen PC, Hu WF, Hu X, Woodward Z, Liu WB, Xiao YM, Liang SP, Liu Y, Liu SJ, Li DW. The PP2A-Aβ gene is regulated by multiple transcriptional factors including Ets-1, SP1/SP3, and RXRα/β. Curr Mol Med. 2012;12(8):982–94.PubMedCrossRefGoogle Scholar
  76. 76.
    Chen HG, Han WJ, Deng M, Qin J, Yuan D, Liu JP, Xiao L, Gong L, Liang S, Zhang J, Liu Y, Li DW. Transcriptional regulation of PP2A-A alpha is mediated by multiple factors including AP-2alpha, CREB, ETS-1, and SP-1. PLoS One. 2009;4(9):e7019.PubMedCentralPubMedCrossRefGoogle Scholar
  77. 77.
    Haeseleer F, Sokal I, Gregory FD, Lee A. Protein phosphatase 2A dephosphorylates CaBP4 and regulates CaBP4 function. Invest Ophthalmol Vis Sci. 2013;54(2):1214–26.PubMedCentralPubMedCrossRefGoogle Scholar
  78. 78.
    Palczewski K, Farber DB, Hargrave PA. Elevated level of protein phosphatase 2A activity in retinas of rd mice. Exp Eye Res. 1991;53:101–5.PubMedCrossRefGoogle Scholar
  79. 79.
    Wang Z, Yang H, Tachado SD, Capó-Aponte JE, Bildin VN, Koziel H, Reinach PS. Phosphatase-mediated crosstalk control of ERK and p38 MAPK signaling in corneal epithelial cells. Invest Ophthalmol Vis Sci. 2006;47:5267–75.PubMedCrossRefGoogle Scholar
  80. 80.
    Tanifuji-Terai N, Terai K, Hayashi Y, Chikama T, Kao WW. Expression of keratin 12 and maturation of corneal epithelium during development and postnatal growth. Invest Ophthalmol Vis Sci. 2006;47:545–51.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Wen-Feng Hu
    • 1
    • 2
  • Xiao-Hui Hu
    • 1
    • 2
  • Weike Ji
    • 1
  • Zhao-Xia Huang
    • 1
    • 2
  • Ling Wang
    • 1
    • 2
  • Zachary Woodward
    • 1
  • Quan Dong Nguyen
    • 1
  • David Wan-Cheng Li
    • 1
    • 2
  1. 1.Department of Ophthalmology and Visual Sciences, Truhlsen Eye Institute, College of MedicineUniversity of Nebraska Medical CenterOmahaUSA
  2. 2.Key Laboratory of Protein Chemistry and Developmental Biology of Education Ministry of China, College of Life SciencesHunan Normal UniversityChangshaChina

Personalised recommendations