PI3K/Akt信号通路参与血小板源性生长因子促进人晶状体上皮细胞移行
|
摘要
后发性白内障指白内障囊外摘除术后,或外伤性白内障部分皮质吸收后所形成的晶状体后囊膜混浊(PCO),是白内障囊外摘除术后影响视力最常见的并发症。有报道,成人白内障术后2年内,有20%-30%的患者因后发障而再度失明,5年内有43%的患者因后发障而行Nd:YAG激光后囊膜切开术。后发性白内障的组织病理学研究表明白内障术后残留的晶状体上皮细胞的增殖、迁移、纤维化生是形成后发障的主要原因,目前有很多此方面的研究,以寻求在这方面找到好的预防和治疗PCO的方法。
目的：晶状体上皮细胞的移行在PCO的形成中起到很重要的作用。目前,其移行的机理还远未阐明。我们研究的目的是探讨PDGF刺激晶状体上皮细胞引起其移行的信号通路和下游分子。
方法：用离体的刮伤愈合实验和跨膜移行实验来研究晶状体上皮细胞的移行。用蛋白印迹分析来研究PDGF刺激HLE-B3细胞对PDGFRβ, PI3K/Akt信号通路和MAPK信号通路活化的影响；对细胞突起分子表达的影响；是否有稳定β-catenin的作用。用免疫荧光分析来研究β-catenin在细胞内分布位置的变化。
结果：PDGF促进HLE-B3细胞的移行,PI3K/Akt信号通路参与其中。通过PDGF/PDGFRβ轴向激活的PI3K/Akt信号通路可以上调细胞突起分子的表达和稳定且改变β-catenin在细胞内的分布,这是是PDGF促进细胞移行的机理之一。
结论：本研究直接证明PI3K/Akt信号通路与人晶状体上皮细胞的移行有关,提供了寻找治疗PCO的新的方法的思路。
PURPOSE Posterior capsular opacification (PCO) is caused partially by the migration of lens epithelial cells. To date, the mechanism of the migration is largely unknown. The purpose of this study was to investigate the effect of platelet-derived growth factor (PDGF)-triggered signaling pathways and its downstream effectors in the migration of lens epithelial cells.
METHODS In vitro scratch-wound healing and transwell migration assays were used to measure the migration of lens epithelial cells. The activation of PDGFRβ, phosphatidylinositol3-kinase (PI3K)/protein kinase B (Akt) and mitogen activation protein kinase (MAPK) pathways, the impact of PDGF treatment on the expression of cell protrusion molecules, and the stabilization of β-catenin were measured by western blotting. The translocation of β-catenin was detected using indirect immunofluorescence.
RESULTS PDGF was found to enhance cell migration, which depended on the PI3K/Akt pathway. The activation of the PI3K/Akt pathway by the PDGF/PDGFRβ axis induced the upregulation of cell protrusion molecules and stabilization and translocation of β-catenin, contributing to enhanced cell migration. CONCLUSION Data from this study directly linked the central PI3K/Akt pathway to lens epithelial cell migration and pointed to new avenues for therapeutic intervention in PCO.
目的：晶状体上皮细胞的移行在PCO的形成中起到很重要的作用。目前,其移行的机理还远未阐明。我们研究的目的是探讨PDGF刺激晶状体上皮细胞引起其移行的信号通路和下游分子。
方法：用离体的刮伤愈合实验和跨膜移行实验来研究晶状体上皮细胞的移行。用蛋白印迹分析来研究PDGF刺激HLE-B3细胞对PDGFRβ, PI3K/Akt信号通路和MAPK信号通路活化的影响；对细胞突起分子表达的影响；是否有稳定β-catenin的作用。用免疫荧光分析来研究β-catenin在细胞内分布位置的变化。
结果：PDGF促进HLE-B3细胞的移行,PI3K/Akt信号通路参与其中。通过PDGF/PDGFRβ轴向激活的PI3K/Akt信号通路可以上调细胞突起分子的表达和稳定且改变β-catenin在细胞内的分布,这是是PDGF促进细胞移行的机理之一。
结论：本研究直接证明PI3K/Akt信号通路与人晶状体上皮细胞的移行有关,提供了寻找治疗PCO的新的方法的思路。
PURPOSE Posterior capsular opacification (PCO) is caused partially by the migration of lens epithelial cells. To date, the mechanism of the migration is largely unknown. The purpose of this study was to investigate the effect of platelet-derived growth factor (PDGF)-triggered signaling pathways and its downstream effectors in the migration of lens epithelial cells.
METHODS In vitro scratch-wound healing and transwell migration assays were used to measure the migration of lens epithelial cells. The activation of PDGFRβ, phosphatidylinositol3-kinase (PI3K)/protein kinase B (Akt) and mitogen activation protein kinase (MAPK) pathways, the impact of PDGF treatment on the expression of cell protrusion molecules, and the stabilization of β-catenin were measured by western blotting. The translocation of β-catenin was detected using indirect immunofluorescence.
RESULTS PDGF was found to enhance cell migration, which depended on the PI3K/Akt pathway. The activation of the PI3K/Akt pathway by the PDGF/PDGFRβ axis induced the upregulation of cell protrusion molecules and stabilization and translocation of β-catenin, contributing to enhanced cell migration. CONCLUSION Data from this study directly linked the central PI3K/Akt pathway to lens epithelial cell migration and pointed to new avenues for therapeutic intervention in PCO.
引文
[1]Chan CM, Fang JY,et al.Lycopene inhibits PDGF-BB-induced retinal pigment epithelial cell migration by suppresion of PI3K/Akt and MAPK pathways.Biochem Biophys Res Commun.2009;388(1):172-6.
[2]He S,Kumar SR,et al.Soluble EphB4 inhibition of PDGF-induced RPE migration in vitro. Invest Ophthalmol Vis Sci.2010;51(1):543-52.
[3]Kim A,Lakshman N,et al.Growth factor regulation of corneal keratocyte differentiation and migration in compressed collagen matrices. Invest Ophthalmol Vis Sci.2010;51(2):864-75.
[4]Pattamatta U,Willcox M,et al.Bovine lactoferrin stimulates human corneal epithelial alkali wound healing in vitro. Invest Ophthalmol Vis Sci.2009;50 (4): 1636-43.
[5]Vij N, Sharma A, Thakkar M, Sinha S, Mohan RR. PDGF-driven proliferation, migration,and IL8 chemokine secretion in human corneal fibroblasts involve JAK2-STAT3 signaling pathway. Mol Vis.2008; 14:1020-1027
[6]Maddala R,Reddy VN,et al.Growth factor induced activation of Rho and Rac GTPase and actin cytoskeletal reorganazation in human lens epithelial cells.Mol Vis.2003;9:329-36.
[7]Kok A, Lovicu FJ, Chamberlain CG, McAvoy JW. Influence of platelet-derived growth factor on lens epithelial cell proliferation and differentiation. Growth Factors 2002; 20:27-34
[8]Chandrasekher G, Sailaja D. Differential Activation of Phosphatidylinositol 3-Kinase Signaling during Proliferation and Differentiation of Lens Epithelial Cells. Invest Ophthalmol Vis Sci.2003; 44:4400-4411.
[9]Ibaraki N, Lin LR, Reddy VN. Effects of growth factors on proliferation and differentiation in human lens epithelial cells in early subculture. Invest Ophthalmol Vis Sci.1995; 36:2304-2312.
[10]Irani C, Goncharova EA, Hunter DS, Waiker CL, Panettieri RA, Krymskaya VP. Phosphatidylinositol 3-kinase but not tuberin is required for PDGF-induced cell migration. Am J Physiol Lung Cell Mol Physiol.2002; 282:L854-862.
[11]Bostrom K. Osteopontin,a missing link in PDGF-induced smooth muscle cell migration. Cardiovasc Res.2007;75:634-635.
[12]Ray S,Gao C,Wyatt K,et al. Platelet-derived growth factor D,tissue-specific expression in the eye,and a key role in control of lens epithelial cell proliferation. J Biol Chem.2005;280(9):8494-8502.
[13]Vinada LM,van Genesen ST,et al.Influence of hormones and growth factors on lens protein composition:the effect of dexamethasone and PDGF-AA.Mol Vis.2003; 9:723-9.
[14]Reneker LW,Overbeek PA.Lens-specific expression of PDGF-A alters lens growth and development.Dev Biol.1996; 180:554-65
[15]Yao K, Tan J, Ye P, Wang K, Xu W, Shen TX, Tang X. Integrin β1-mediated signaling is involved in transforming growth factor-β2-promoted migration in human lens epithelial cells. Mol Vis.2007; 13:1769-1776.
[16]Iyengar L, Patkunanathan B, Lynch OT, McAvoy JW, Rasko JE, Lovicu FJ. Aqueous humour-and growth factor-induced lens cell proliferation is dependent on MAPK/ERK1/2 and Akt/PI3-K signaling. Exp Eye Res.2006; 83:667-678.
[17]Chen KC, Zhou Y, Xing K, Krysan K, Lou MF. Plate derived growth factor(PDGF)-induced reactive oxygen species in the lens epithelial cells:the redox signaling. Exp Eye Res.2004;78:1057-1067.
[18]Filippa N, Sable CL, Filloux C, Hemmings B, Van Obberghen E. Mechanism of Protein Kinase B Activation by Cyclic AMP-Dependent Protein Kinase. Mol Cell Biol. 1999;19:4989-5000.
[19]Fleming TP, Song Z, Andley UP. Expression of growth control and differentiation genes in human lens epithelial cells with extended life span. Invest Ophthalmol Vis Sci.1998; 39:1387-1398.
[20]Mejillano MR, Kojima S, Applewhite DA, Gertler FB, Svitkina TM, Borisy GG Lamellipodial Versus Filopodial Mode of the Actin Nanomachinery:Pivotal Role of the Filament Barbed End. Cell.2004; 118:363-373.
[21]Wang C, Navab R, Iakovlev V, Leng Y, Zhang J, Tsao MS, Siminovitch K, McCready DR, Done SJ. Abelson Interactor Protein-1 Positively Regulates Breast Cancer Cell Proliferation, Migration, and Invasion. Mol Cancer Res.2007; 5: 1031-1039.
[22]Maddala R, Rao VP. alpha-Crystallin localizes to the leading edges of migrating lens epithelial cells. Exp Cell Res.2005; 306:203-215.
[23]Muller T, Bain G, Wang X, Papkoff J. Regulation of Epithelial Cell Migration and Tumor Formation by β-catenin Signaling. Exp Cell Res.2002; 280:119-133.
[24]Liou GI,Matragoon S, Samuel S, Behzadian MA, Tsai NT, Gu X, Roon P, Hunt DM, Hunt RC, Caldwell RB, Marcus DM. MAP kinase and β-catenin signaling in HGF induced RPE migration. Mol Vis.2002; 8:483-493.
[25]Fang D, Hawke D, Zheng Y, Xia Y, Meisenhelder J, Nika H, Mills GB, Kobayashi R, Hunter T, Lu Z. Phosphorylation of β-catenin by AKT Promotes β-catenin Transcri-ptional Activity. JBiol Chem.2001; 282:11221-11229.
[26]Goncharova EA, Ammit AJ, Irani C, Carroll RG, Eszterhas AJ, Panettieri RA, Krymskaya VP. PI3K is required for proliferation and migration of human pulmonary vascular smooth muscle cells. Am J Physiol Lung Cell Mol Physiol.2002; 283:L354-363.
[27]Onishi K, Higuchi M, Asakura T, Masuyama N, Gotoh Y. The PI3K-Akt pathway promotes microtubule stabilization in migrating fibroblasts. Genes Cells.2007; 12:535-546.
[28]Kim SJ, Kim SY, Kwon CH, Kim YK. Differential effect of FGF and PDGF on cell proliferation and migration in osteoblastic cells. Growth Factors.2007; 25:77-86
[29]Fleming TP, Song Z, Andley UP. Expression of growth control and differentiation genes in human lens epithelial cells with extended life span. Invest Ophthalmol Vis Sci.1998; 39:1387-1398.
[30]Yap AS, Brieher WM, Gumbiner BM. Molecular and functional analysis of cadherin-based adherens junctions. Annu Rev Cell Dev Biol.1997; 13:119-146.
[31]Polakis P. Wnt signaling and cancer. Genes Dev.2000; 14:1837-1851.
[32]Peifer M., Polakis P. Wnt signaling in oncogenesis and embryogenesis-A look outside the nucleus. Science.2000; 287:1606-1609
[33]Kikuchi A. Regulation of beta-catenin signaling in the Wnt pathway. Biochem Biophys Res Commun.2000;268:243-248.
[34]Muller T, Bain G, Wang X, Papkoff J. Regulation of Epithelial Cell Migration and Tumor Formation by β-catenin Signaling. Exp Cell Res.2002; 280:119-133.
[35]Papkoff J, Rubinfeld B, Schryver B, Polakis P. Wnt-1 regulates free pools of catenins and stabilizes APC-catenin complexes. Mol Cell Biol.1996; 16:2128-2134.
[36]Liou GI,Matragoon S, Samuel S, Behzadian MA, Tsai NT, Gu X, Roon P, Hunt DM, Hunt RC, Caldwell RB, Marcus DM. MAP kinase and β-catenin signaling in HGF induced RPE migration. Mol Vis.2002; 8:483-493.
[37]Daniel JM, Reynolds AB. Tyrosine phosphorylation and cadherin/catenin function. Bioessays.1997:19:883-891.
[38]Muller T, Choidas A, Reichmann E, Ullrich A. Phosphorylation and free pool of beta-catenin are regulated by tyrosine kinases and tyrosine phosphatases during epithelial cell migration. JBiol Chem.1999; 274:10173-10183.
[39]Grosschedl R, Giese K, Pagel J. HMG domain proteins:architectural elements in the assembly of nucleoprotein structures. Trends Genet.1994; 10:94-100.
[40]Behrens J, von Kries JP, Kuhl M, Bruhn L, Wedlich D, Grosschedl R, Birchmeier W. Functional interaction of beta-catenin with the transcription factor LEF-1. Nature.1996; 382:638-642.
[41]Molenaar M, van de Wetering M, Oosterwegel M, Peterson-Maduro J, Godsave S, Korinek V, Roose J, Destree O, Clevers H. XTcf-3 transcription factor mediates beta-catenin-induced axis formation in Xenopus embryos. Cell.1996; 86:391-399.
[42]Dale TC. Signal transduction by the Wnt family of ligands. Biochem J.1998; 329:209-223.
[43]Brown JD, Moon RT. Wnt signaling:why is everything so negative? Curr Opin Cell Biol.1998; 10:182-187.
[44]Maddala R, Rao VP. alpha-Crystallin localizes to the leading edges of migrating lens epithelial cells. Exp Cell Res.2005; 306:203-215.
[45]Grove M, Demyanenko G, Echarri A, Zipfel PA, Quiroz ME, Rodriguiz RM, Playford M, Martensen SA, Robinson MR, Wetsel WC, Maness PF, Pendergast AM. ABI2-deficient mice exhibit defective cell migration, aberrant dendritic spine morphogenesis, and deficits in learning and memory. Mol Cell Biol.2004; 24: 10905-10922.
[46]Stradal T, Courtney KD, Rottner K, Hahne P, Small JV, Pendergast AM. The Abl interactor proteins localize to sites of actin polymerization at the tips of lamellipodia and filopodia. Curr Biol.2001; 11:891-895.
[47]Wang C, Navab R, Iakovlev V, Leng Y, Zhang J, Tsao MS, Siminovitch K, McCready DR, Done SJ. Abelson Interactor Protein-1 Positively Regulates Breast Cancer Cell Proliferation, Migration, and Invasion. Mol Cancer Res.2007; 5: 1031-1039.
[48]Maddala R, Rao VP. alpha-Crystallin localizes to the leading edges of migrating lens epithelial cells. Exp Cell Res.2005; 306:203-215.
[1]Ibaraki N. A brighter future for cataract surgery. Nat Med,1997;3(9):958-960
[2]Sundelin K, Sjostrand J. Posterior capsule opacification 5 years after extracapsular cataract extraction. J Cataract Refract Surg,1999;25(2):246-250
[3]Ross R,Glomset J,Kariya B,Harker L,et al.A platelet-dependent serum factor that stimulates the proliferation of arterial smooth muscle ceiis in vitro.Pro Natl Acad Sci 1974;71:1207-1210.
[4]Heldin CH,Westernmark B.Mechanism of action and in vivo role of platelet-derived growth factor.Physxol Rev 1999;79:1283-1316.
[5]Li X,Ponten A,Aase K,,et al.PDGF-C is a new protease-activated ligand for the PDGF alpha-receptor.Nat Cell Biol 2000;2:302-309.
[6]Bergsten E,Uutela M,et al.PDGF-D is a specific, protease-activated ligand for the PDGF beta receptor.Nat Cell Biol 2001;3:512-516.
[7]LaRochelle WJ,Jeffers M,et al.PDGF-D,a new protease-activated ligand growth factor.Nat Cell Biol 2001;3:517-521.
[8]Johnsson A,Heldin CH,et al.The c-sis gene encodes a precursor of the B chain of platelet-derived growth factor.EMBO J 1984;3:921-928.
[9]Uutela M,Lauren J,et al.Chromosomal location,exon structure,and vascular expression patterns of the human PDGFC and PDGFD genes.Circulation 2001;103: 2241-2247.
[10]Heldin CH, WESTERNMARK B (April 1989). Platelet-derived growth factor: three isoforms and two receptor types. Trends Genet.5 (4):108-11..
[11]Heldin CH, Ostman A, Eriksson A, Siegbahn A, Claesson-Welsh L, Westermark B (March 1992). Platelet-derived growth factor:isoform-specific signalling via heterodimeric or homodimeric receptor complexes. Kidney Int.41 (3):571-4.
[12]REILLY JT. Class Ⅲ receptor tyrosine kinases:role in leukaemogenesis[J]. Br J Haematol,2002,116:744-757.
[13]Debra GG,Mephan ED,James W. Platelet-derived growth factorC(PDGF-C),novel growth factor that binds to PDGF and receotor[J].Biol Chem 2001;276:27404-27414.
[14]Aaronson DS, Horvoth CM.A road map for those who don't know JAK/STAT. Science,2002,296:1653-1655.
[15]Singh SR, Chen X, Hou SX.JAk/STAT signaling regulates tissue outgrowth and male germline stem cell fate in Drosophila.Cell Res,2005,15:1-5.
[16]Kawano H, Kim S, Ohta K, et al.Differential contribution of three mitogen activated protein kinases to PDGF BB induced mesangial cell proliferation and gene expression.J Am Soc Nephrol,2003,14:584-592.
[17]Carloni V, Pinzani M, Ciusti S, et al.Tyrosine phosphorylation of focal adhesion kinase by PDGF is dependent on ras in human hepatic stellate cells. Hepatology, 2000,31:131-140.
[18]18 Garrington TP, Johnson GL.Organization and regulation of mitogen activated protein kinase signaling pathways.Curr Opin Cell Biol,1999,11:211-218.
[19]Marcantonio JM, Vrensen GF. Cell biology of posterior capsular opacification. Eye,1999;13(Pt3b):484-488
[20]Ke Yao, Jian Tan, PanPan Ye,KaiJun Wang,Wen Xu,XingChao Shen Tu,XiaJing Tang. Integrin β1-mediated signaling is involved in transforming growth factor-β2-promoted migration in human lens epithelial cells.Molecular Vision,2007; 13:1769-1776.
[21]Verrecchia F, Mauviel A. Transforming growth factor-bsignaling through the Smad pathway:role in extracellular matrix gene expression and regulation. J Invest Dermatol,2002;118:211-215
[22]Majima K. Effect of epidermal growth factor upon morphological changes of human lens epithelial cells. Ophthalmologica,1998;212(4):250-256
[23]Nishi O, Nishi K, Fujiwara T, Shirasawa E, Ohmoto Y. Effects of the cytokines on the proliferation of and collagen synthesis by human cataract lens epithelial cells. Br J Ophthalmol,1996,80(1):63-68
[24]Bates RC, Mercurio AM.Tumor necrosis factor-alpha stimulates the epithelial- to-mesenchymal transition of human colonic organoids. Mol Biol Cell,2003; 14 (5): 1790-1800.
[25]Prada J, Ngo-Tu T, Baatz H, Hartmann C, Pleyer U. Detection of tumor necrosis factor alpha and interleukin 1 alpha gene expression in human lens epithelial cells. J Cataract Refract Surg,2000;26(1):114-117
[26]hang XH, Sun HM, Yuan JQ. Extracellular matrix production of lens epithelial cells. J Cataract Refract Surg,2001;27(8):1303-1309
[27]Spalton DJ.Posterior capsular opacification after cataract surgery.Eye 1999; 13: 489-92.
[28]Vij N, Sharma A, Thakkar M, Sinha S, Mohan RR. PDGF-driven proliferation, migration,and IL8 chemokine secretion in human corneal fibroblasts involve JAK2-STAT3 signaling pathway. Mol Vis.2008; 14:1020-1027
[29]Goncharova EA, Ammit AJ, Irani C, Carroll RG, Eszterhas AJ, Panettieri RA, Krymskaya VP. PI3K is required for proliferation and migration of human pulmonary vascular smooth muscle cells. Am J Physiol Lung Cell Mol Physiol. 2002;283:L354-363.
[30]Katso R, Okkenhaug K, Ahmadi K, White S, Timms J, and Waterfield MD. Cellular function of phosphoinositide 3-kinases:implications for development, homeostasis, and cancer. Annu Rev Cell Dev Biol.2001; 17:615-675.
[31]Ibaraki N, Lin LR, Reddy VN. Effects of growth factors on proliferation and bdifferentiation in human lens epithelial cells in early subculture. Invest Ophthalmol Vis Sci,1995;36(11):2304-2312
[32]Reneker LW, Overbeek PA. Lens-specific expression of PDGF-A alters lens growth and development. Dev Biol,1996;180(2):554-565
[33]Wunderlich K,Knorr M.Effect of platelet-derived growth factor PDGF on replic ation of cultivated bovine lens epithelial cells.Ophthalmologe 1994;91(1):98-102.
[34]Kok A,Lovicu FJ,Chamberlain CG,McAvoy JW.Influence of platelet-derived growth factor on lens epithelial cell proliferation and differention.Growth Factors,2002;20 (1):27-34.
[35]Mansfield KJ,Cerra A,Chamberlain CG.FGF-2 counteracts loss of TGFbeta affected cells from rat lens explants:implication for PCO(after cataract).Mol Vis.2004;10:521-532
[36]Wang Q,McAvoy JW,Lovicu FJ.Growth factor signaling in vitreous humor-induced lens fiber differentiation.Invest Ophthalmol Vis Sci.2010;51(7):3599-3610.
[37]Iyengar L,Patkunanathan B, Lynch OT, McAvoy JW, Rasko JE, Lovicu FJ. Aqueous humour-and growth factor-induced lens cell proliferation is dependent on MAPK/ERK1/2 and Akt/PI3-K signalling.Exp Eye Res.2006;83(3):667-78.
[38]Chen KC,Zhou Y,Zhang W,Lou MF.Control of PDGF-induced reactive oxygen species generation and signal transduction in human lens epithelial cells.Mol Vis.2007;13:374-387.
[39]Zhang W,Wang Y,et al.The positive feedback role of arachidonic acid in the platelet-derived growth factor-induced signaling in lens epithelial cells.Mol Vis. 2006;12:821-831.
[40]Wang Y,Lou MF.The regulation of NADPH oxidase and its association with cell proliferation in human lens epithelial cells. Invest Ophthalmol Vis Sci.2009; 50(5):2291-2300.
[41]Ray S,Gao C,Wyatt K,et al. Platelet-derived growth factor D,tissue-specific expression in the eye,and a key role in control of lens epithelial cell proliferation. J Biol Chem.2005;280(9):8494-8502.
[42]Vinada LM,van Genesen ST,et al.Influence of hormones and growth factors on lens protein composition:the effect of dexamethasone and PDGF-AA.Mol Vis.2003; 9:723-9.
[43]Reneker LW,Overbeek PA.Lens-specific expression of PDGF-A alters lens growth and development.Dev Biol.1996;180:554-65
[44]Knorr M,Wonderlich K,et al.Lens epithelial cell response to isoforms of platelet-derived growth factor.Graefes Arch Clin Exp Ophthalmol.1993; 231 (7):424-8.
[2]He S,Kumar SR,et al.Soluble EphB4 inhibition of PDGF-induced RPE migration in vitro. Invest Ophthalmol Vis Sci.2010;51(1):543-52.
[3]Kim A,Lakshman N,et al.Growth factor regulation of corneal keratocyte differentiation and migration in compressed collagen matrices. Invest Ophthalmol Vis Sci.2010;51(2):864-75.
[4]Pattamatta U,Willcox M,et al.Bovine lactoferrin stimulates human corneal epithelial alkali wound healing in vitro. Invest Ophthalmol Vis Sci.2009;50 (4): 1636-43.
[5]Vij N, Sharma A, Thakkar M, Sinha S, Mohan RR. PDGF-driven proliferation, migration,and IL8 chemokine secretion in human corneal fibroblasts involve JAK2-STAT3 signaling pathway. Mol Vis.2008; 14:1020-1027
[6]Maddala R,Reddy VN,et al.Growth factor induced activation of Rho and Rac GTPase and actin cytoskeletal reorganazation in human lens epithelial cells.Mol Vis.2003;9:329-36.
[7]Kok A, Lovicu FJ, Chamberlain CG, McAvoy JW. Influence of platelet-derived growth factor on lens epithelial cell proliferation and differentiation. Growth Factors 2002; 20:27-34
[8]Chandrasekher G, Sailaja D. Differential Activation of Phosphatidylinositol 3-Kinase Signaling during Proliferation and Differentiation of Lens Epithelial Cells. Invest Ophthalmol Vis Sci.2003; 44:4400-4411.
[9]Ibaraki N, Lin LR, Reddy VN. Effects of growth factors on proliferation and differentiation in human lens epithelial cells in early subculture. Invest Ophthalmol Vis Sci.1995; 36:2304-2312.
[10]Irani C, Goncharova EA, Hunter DS, Waiker CL, Panettieri RA, Krymskaya VP. Phosphatidylinositol 3-kinase but not tuberin is required for PDGF-induced cell migration. Am J Physiol Lung Cell Mol Physiol.2002; 282:L854-862.
[11]Bostrom K. Osteopontin,a missing link in PDGF-induced smooth muscle cell migration. Cardiovasc Res.2007;75:634-635.
[12]Ray S,Gao C,Wyatt K,et al. Platelet-derived growth factor D,tissue-specific expression in the eye,and a key role in control of lens epithelial cell proliferation. J Biol Chem.2005;280(9):8494-8502.
[13]Vinada LM,van Genesen ST,et al.Influence of hormones and growth factors on lens protein composition:the effect of dexamethasone and PDGF-AA.Mol Vis.2003; 9:723-9.
[14]Reneker LW,Overbeek PA.Lens-specific expression of PDGF-A alters lens growth and development.Dev Biol.1996; 180:554-65
[15]Yao K, Tan J, Ye P, Wang K, Xu W, Shen TX, Tang X. Integrin β1-mediated signaling is involved in transforming growth factor-β2-promoted migration in human lens epithelial cells. Mol Vis.2007; 13:1769-1776.
[16]Iyengar L, Patkunanathan B, Lynch OT, McAvoy JW, Rasko JE, Lovicu FJ. Aqueous humour-and growth factor-induced lens cell proliferation is dependent on MAPK/ERK1/2 and Akt/PI3-K signaling. Exp Eye Res.2006; 83:667-678.
[17]Chen KC, Zhou Y, Xing K, Krysan K, Lou MF. Plate derived growth factor(PDGF)-induced reactive oxygen species in the lens epithelial cells:the redox signaling. Exp Eye Res.2004;78:1057-1067.
[18]Filippa N, Sable CL, Filloux C, Hemmings B, Van Obberghen E. Mechanism of Protein Kinase B Activation by Cyclic AMP-Dependent Protein Kinase. Mol Cell Biol. 1999;19:4989-5000.
[19]Fleming TP, Song Z, Andley UP. Expression of growth control and differentiation genes in human lens epithelial cells with extended life span. Invest Ophthalmol Vis Sci.1998; 39:1387-1398.
[20]Mejillano MR, Kojima S, Applewhite DA, Gertler FB, Svitkina TM, Borisy GG Lamellipodial Versus Filopodial Mode of the Actin Nanomachinery:Pivotal Role of the Filament Barbed End. Cell.2004; 118:363-373.
[21]Wang C, Navab R, Iakovlev V, Leng Y, Zhang J, Tsao MS, Siminovitch K, McCready DR, Done SJ. Abelson Interactor Protein-1 Positively Regulates Breast Cancer Cell Proliferation, Migration, and Invasion. Mol Cancer Res.2007; 5: 1031-1039.
[22]Maddala R, Rao VP. alpha-Crystallin localizes to the leading edges of migrating lens epithelial cells. Exp Cell Res.2005; 306:203-215.
[23]Muller T, Bain G, Wang X, Papkoff J. Regulation of Epithelial Cell Migration and Tumor Formation by β-catenin Signaling. Exp Cell Res.2002; 280:119-133.
[24]Liou GI,Matragoon S, Samuel S, Behzadian MA, Tsai NT, Gu X, Roon P, Hunt DM, Hunt RC, Caldwell RB, Marcus DM. MAP kinase and β-catenin signaling in HGF induced RPE migration. Mol Vis.2002; 8:483-493.
[25]Fang D, Hawke D, Zheng Y, Xia Y, Meisenhelder J, Nika H, Mills GB, Kobayashi R, Hunter T, Lu Z. Phosphorylation of β-catenin by AKT Promotes β-catenin Transcri-ptional Activity. JBiol Chem.2001; 282:11221-11229.
[26]Goncharova EA, Ammit AJ, Irani C, Carroll RG, Eszterhas AJ, Panettieri RA, Krymskaya VP. PI3K is required for proliferation and migration of human pulmonary vascular smooth muscle cells. Am J Physiol Lung Cell Mol Physiol.2002; 283:L354-363.
[27]Onishi K, Higuchi M, Asakura T, Masuyama N, Gotoh Y. The PI3K-Akt pathway promotes microtubule stabilization in migrating fibroblasts. Genes Cells.2007; 12:535-546.
[28]Kim SJ, Kim SY, Kwon CH, Kim YK. Differential effect of FGF and PDGF on cell proliferation and migration in osteoblastic cells. Growth Factors.2007; 25:77-86
[29]Fleming TP, Song Z, Andley UP. Expression of growth control and differentiation genes in human lens epithelial cells with extended life span. Invest Ophthalmol Vis Sci.1998; 39:1387-1398.
[30]Yap AS, Brieher WM, Gumbiner BM. Molecular and functional analysis of cadherin-based adherens junctions. Annu Rev Cell Dev Biol.1997; 13:119-146.
[31]Polakis P. Wnt signaling and cancer. Genes Dev.2000; 14:1837-1851.
[32]Peifer M., Polakis P. Wnt signaling in oncogenesis and embryogenesis-A look outside the nucleus. Science.2000; 287:1606-1609
[33]Kikuchi A. Regulation of beta-catenin signaling in the Wnt pathway. Biochem Biophys Res Commun.2000;268:243-248.
[34]Muller T, Bain G, Wang X, Papkoff J. Regulation of Epithelial Cell Migration and Tumor Formation by β-catenin Signaling. Exp Cell Res.2002; 280:119-133.
[35]Papkoff J, Rubinfeld B, Schryver B, Polakis P. Wnt-1 regulates free pools of catenins and stabilizes APC-catenin complexes. Mol Cell Biol.1996; 16:2128-2134.
[36]Liou GI,Matragoon S, Samuel S, Behzadian MA, Tsai NT, Gu X, Roon P, Hunt DM, Hunt RC, Caldwell RB, Marcus DM. MAP kinase and β-catenin signaling in HGF induced RPE migration. Mol Vis.2002; 8:483-493.
[37]Daniel JM, Reynolds AB. Tyrosine phosphorylation and cadherin/catenin function. Bioessays.1997:19:883-891.
[38]Muller T, Choidas A, Reichmann E, Ullrich A. Phosphorylation and free pool of beta-catenin are regulated by tyrosine kinases and tyrosine phosphatases during epithelial cell migration. JBiol Chem.1999; 274:10173-10183.
[39]Grosschedl R, Giese K, Pagel J. HMG domain proteins:architectural elements in the assembly of nucleoprotein structures. Trends Genet.1994; 10:94-100.
[40]Behrens J, von Kries JP, Kuhl M, Bruhn L, Wedlich D, Grosschedl R, Birchmeier W. Functional interaction of beta-catenin with the transcription factor LEF-1. Nature.1996; 382:638-642.
[41]Molenaar M, van de Wetering M, Oosterwegel M, Peterson-Maduro J, Godsave S, Korinek V, Roose J, Destree O, Clevers H. XTcf-3 transcription factor mediates beta-catenin-induced axis formation in Xenopus embryos. Cell.1996; 86:391-399.
[42]Dale TC. Signal transduction by the Wnt family of ligands. Biochem J.1998; 329:209-223.
[43]Brown JD, Moon RT. Wnt signaling:why is everything so negative? Curr Opin Cell Biol.1998; 10:182-187.
[44]Maddala R, Rao VP. alpha-Crystallin localizes to the leading edges of migrating lens epithelial cells. Exp Cell Res.2005; 306:203-215.
[45]Grove M, Demyanenko G, Echarri A, Zipfel PA, Quiroz ME, Rodriguiz RM, Playford M, Martensen SA, Robinson MR, Wetsel WC, Maness PF, Pendergast AM. ABI2-deficient mice exhibit defective cell migration, aberrant dendritic spine morphogenesis, and deficits in learning and memory. Mol Cell Biol.2004; 24: 10905-10922.
[46]Stradal T, Courtney KD, Rottner K, Hahne P, Small JV, Pendergast AM. The Abl interactor proteins localize to sites of actin polymerization at the tips of lamellipodia and filopodia. Curr Biol.2001; 11:891-895.
[47]Wang C, Navab R, Iakovlev V, Leng Y, Zhang J, Tsao MS, Siminovitch K, McCready DR, Done SJ. Abelson Interactor Protein-1 Positively Regulates Breast Cancer Cell Proliferation, Migration, and Invasion. Mol Cancer Res.2007; 5: 1031-1039.
[48]Maddala R, Rao VP. alpha-Crystallin localizes to the leading edges of migrating lens epithelial cells. Exp Cell Res.2005; 306:203-215.
[1]Ibaraki N. A brighter future for cataract surgery. Nat Med,1997;3(9):958-960
[2]Sundelin K, Sjostrand J. Posterior capsule opacification 5 years after extracapsular cataract extraction. J Cataract Refract Surg,1999;25(2):246-250
[3]Ross R,Glomset J,Kariya B,Harker L,et al.A platelet-dependent serum factor that stimulates the proliferation of arterial smooth muscle ceiis in vitro.Pro Natl Acad Sci 1974;71:1207-1210.
[4]Heldin CH,Westernmark B.Mechanism of action and in vivo role of platelet-derived growth factor.Physxol Rev 1999;79:1283-1316.
[5]Li X,Ponten A,Aase K,,et al.PDGF-C is a new protease-activated ligand for the PDGF alpha-receptor.Nat Cell Biol 2000;2:302-309.
[6]Bergsten E,Uutela M,et al.PDGF-D is a specific, protease-activated ligand for the PDGF beta receptor.Nat Cell Biol 2001;3:512-516.
[7]LaRochelle WJ,Jeffers M,et al.PDGF-D,a new protease-activated ligand growth factor.Nat Cell Biol 2001;3:517-521.
[8]Johnsson A,Heldin CH,et al.The c-sis gene encodes a precursor of the B chain of platelet-derived growth factor.EMBO J 1984;3:921-928.
[9]Uutela M,Lauren J,et al.Chromosomal location,exon structure,and vascular expression patterns of the human PDGFC and PDGFD genes.Circulation 2001;103: 2241-2247.
[10]Heldin CH, WESTERNMARK B (April 1989). Platelet-derived growth factor: three isoforms and two receptor types. Trends Genet.5 (4):108-11..
[11]Heldin CH, Ostman A, Eriksson A, Siegbahn A, Claesson-Welsh L, Westermark B (March 1992). Platelet-derived growth factor:isoform-specific signalling via heterodimeric or homodimeric receptor complexes. Kidney Int.41 (3):571-4.
[12]REILLY JT. Class Ⅲ receptor tyrosine kinases:role in leukaemogenesis[J]. Br J Haematol,2002,116:744-757.
[13]Debra GG,Mephan ED,James W. Platelet-derived growth factorC(PDGF-C),novel growth factor that binds to PDGF and receotor[J].Biol Chem 2001;276:27404-27414.
[14]Aaronson DS, Horvoth CM.A road map for those who don't know JAK/STAT. Science,2002,296:1653-1655.
[15]Singh SR, Chen X, Hou SX.JAk/STAT signaling regulates tissue outgrowth and male germline stem cell fate in Drosophila.Cell Res,2005,15:1-5.
[16]Kawano H, Kim S, Ohta K, et al.Differential contribution of three mitogen activated protein kinases to PDGF BB induced mesangial cell proliferation and gene expression.J Am Soc Nephrol,2003,14:584-592.
[17]Carloni V, Pinzani M, Ciusti S, et al.Tyrosine phosphorylation of focal adhesion kinase by PDGF is dependent on ras in human hepatic stellate cells. Hepatology, 2000,31:131-140.
[18]18 Garrington TP, Johnson GL.Organization and regulation of mitogen activated protein kinase signaling pathways.Curr Opin Cell Biol,1999,11:211-218.
[19]Marcantonio JM, Vrensen GF. Cell biology of posterior capsular opacification. Eye,1999;13(Pt3b):484-488
[20]Ke Yao, Jian Tan, PanPan Ye,KaiJun Wang,Wen Xu,XingChao Shen Tu,XiaJing Tang. Integrin β1-mediated signaling is involved in transforming growth factor-β2-promoted migration in human lens epithelial cells.Molecular Vision,2007; 13:1769-1776.
[21]Verrecchia F, Mauviel A. Transforming growth factor-bsignaling through the Smad pathway:role in extracellular matrix gene expression and regulation. J Invest Dermatol,2002;118:211-215
[22]Majima K. Effect of epidermal growth factor upon morphological changes of human lens epithelial cells. Ophthalmologica,1998;212(4):250-256
[23]Nishi O, Nishi K, Fujiwara T, Shirasawa E, Ohmoto Y. Effects of the cytokines on the proliferation of and collagen synthesis by human cataract lens epithelial cells. Br J Ophthalmol,1996,80(1):63-68
[24]Bates RC, Mercurio AM.Tumor necrosis factor-alpha stimulates the epithelial- to-mesenchymal transition of human colonic organoids. Mol Biol Cell,2003; 14 (5): 1790-1800.
[25]Prada J, Ngo-Tu T, Baatz H, Hartmann C, Pleyer U. Detection of tumor necrosis factor alpha and interleukin 1 alpha gene expression in human lens epithelial cells. J Cataract Refract Surg,2000;26(1):114-117
[26]hang XH, Sun HM, Yuan JQ. Extracellular matrix production of lens epithelial cells. J Cataract Refract Surg,2001;27(8):1303-1309
[27]Spalton DJ.Posterior capsular opacification after cataract surgery.Eye 1999; 13: 489-92.
[28]Vij N, Sharma A, Thakkar M, Sinha S, Mohan RR. PDGF-driven proliferation, migration,and IL8 chemokine secretion in human corneal fibroblasts involve JAK2-STAT3 signaling pathway. Mol Vis.2008; 14:1020-1027
[29]Goncharova EA, Ammit AJ, Irani C, Carroll RG, Eszterhas AJ, Panettieri RA, Krymskaya VP. PI3K is required for proliferation and migration of human pulmonary vascular smooth muscle cells. Am J Physiol Lung Cell Mol Physiol. 2002;283:L354-363.
[30]Katso R, Okkenhaug K, Ahmadi K, White S, Timms J, and Waterfield MD. Cellular function of phosphoinositide 3-kinases:implications for development, homeostasis, and cancer. Annu Rev Cell Dev Biol.2001; 17:615-675.
[31]Ibaraki N, Lin LR, Reddy VN. Effects of growth factors on proliferation and bdifferentiation in human lens epithelial cells in early subculture. Invest Ophthalmol Vis Sci,1995;36(11):2304-2312
[32]Reneker LW, Overbeek PA. Lens-specific expression of PDGF-A alters lens growth and development. Dev Biol,1996;180(2):554-565
[33]Wunderlich K,Knorr M.Effect of platelet-derived growth factor PDGF on replic ation of cultivated bovine lens epithelial cells.Ophthalmologe 1994;91(1):98-102.
[34]Kok A,Lovicu FJ,Chamberlain CG,McAvoy JW.Influence of platelet-derived growth factor on lens epithelial cell proliferation and differention.Growth Factors,2002;20 (1):27-34.
[35]Mansfield KJ,Cerra A,Chamberlain CG.FGF-2 counteracts loss of TGFbeta affected cells from rat lens explants:implication for PCO(after cataract).Mol Vis.2004;10:521-532
[36]Wang Q,McAvoy JW,Lovicu FJ.Growth factor signaling in vitreous humor-induced lens fiber differentiation.Invest Ophthalmol Vis Sci.2010;51(7):3599-3610.
[37]Iyengar L,Patkunanathan B, Lynch OT, McAvoy JW, Rasko JE, Lovicu FJ. Aqueous humour-and growth factor-induced lens cell proliferation is dependent on MAPK/ERK1/2 and Akt/PI3-K signalling.Exp Eye Res.2006;83(3):667-78.
[38]Chen KC,Zhou Y,Zhang W,Lou MF.Control of PDGF-induced reactive oxygen species generation and signal transduction in human lens epithelial cells.Mol Vis.2007;13:374-387.
[39]Zhang W,Wang Y,et al.The positive feedback role of arachidonic acid in the platelet-derived growth factor-induced signaling in lens epithelial cells.Mol Vis. 2006;12:821-831.
[40]Wang Y,Lou MF.The regulation of NADPH oxidase and its association with cell proliferation in human lens epithelial cells. Invest Ophthalmol Vis Sci.2009; 50(5):2291-2300.
[41]Ray S,Gao C,Wyatt K,et al. Platelet-derived growth factor D,tissue-specific expression in the eye,and a key role in control of lens epithelial cell proliferation. J Biol Chem.2005;280(9):8494-8502.
[42]Vinada LM,van Genesen ST,et al.Influence of hormones and growth factors on lens protein composition:the effect of dexamethasone and PDGF-AA.Mol Vis.2003; 9:723-9.
[43]Reneker LW,Overbeek PA.Lens-specific expression of PDGF-A alters lens growth and development.Dev Biol.1996;180:554-65
[44]Knorr M,Wonderlich K,et al.Lens epithelial cell response to isoforms of platelet-derived growth factor.Graefes Arch Clin Exp Ophthalmol.1993; 231 (7):424-8.