Dapper1是核质穿梭蛋白并在细胞核内抑制Wnt信号
摘要
由β-catenin和LEF/TCF家族转录因子激活的经典Wnt信号通路,通过调控细胞增殖、分化以及存活过程中所涉及的重要基因的表达在胚胎发育和癌症发生过程中起着重要的作用。Dapper1(Dpr1),作为Dishevelled的相互作用因子,被认为可以通过促进Dishevelled降解来调控Wnt信号。本研究中我们证明了Dpr1穿梭于细胞质和细胞核之间。尽管过量表达的Dpr1被发现主要存在于细胞质中,内源的Dpr1定位于整个细胞并且Wnt1刺激能够促进它的细胞质聚集。Exportin抑制剂Leptomycin B处理能够引起内源以及过量表达Dpr1聚集于细胞核中,表明Dpr1穿梭于细胞质和细胞核之间。我们进而发现了Dpr1的入核信号NLS以及出核信号NES。利用报告基因实验以及体内斑马鱼胚胎实验,我们证明了细胞核定位的Dpr1突变体依然保持抑制Wnt信号的能力。进而我们发现Dpr1分别和β-catenin以及LEF1相互作用并破坏它们之间复合物的形成。此外,Dpr1可以和HDAC1结合并增强LEF1-HDAC1相互作用。总之,我们的发现提示Dpr1在细胞核内通过保持LEF1处于转录抑制状态来负调控Wnt/β-catenin信号的基础活性。因而,Dpr1既能在细胞质又能在细胞核内调控Wnt/β-catenin信号。
Wnt signaling, via the activation of the canonicalβ-catenin and lymphoid enhancer factor/T-cell factor (LEF/TCF) pathway, plays an important role in embryogenesis and cancer development by regulating the expression of genes involved in cell proliferation, differentiation and survival. Dapper1 (Dpr1), as a Dishevelled interactor, has been suggested to modulate Wnt signaling by promoting Dishevelled degradation. Here, we provide evidence that Dpr1 shuttles between the cytoplasm and the nucleus. Although overexpressed Dpr1 was mainly found in the cytoplasm, endogenous Dpr1 were localized over the cell and Wnt1 induced its nuclear export. Treatment with leptomycin B induced nuclear accumulation of both endogenous and overexpressed Dpr1, suggesting that Dpr1 shuttles between the cytoplasma and the nucleus. We further identified the nuclear localization signal and the nuclear export signal within Dpr1. Using reporter assay and in vivo zebrafish embryo assay, we demonstrated that the forced nuclear localization of Dpr1 possessed the ability to antagonize Wnt signaling. Dpr1 interacted withβ-catenin and LEF1 and disrupted their complex formation. Furthermore, Dpr1 could associate with HDAC1 and enhance the LEF1-HDAC1 interaction. Together, our findings suggest that Dpr1 negatively modulates the basal activity of Wnt/β-catenin signaling in the nucleus by keeping LEF1 in the repressive state. Thus, Dpr1 controls Wnt/β-catenin signaling in both the cytoplasm and the nucleus.
Wnt signaling, via the activation of the canonicalβ-catenin and lymphoid enhancer factor/T-cell factor (LEF/TCF) pathway, plays an important role in embryogenesis and cancer development by regulating the expression of genes involved in cell proliferation, differentiation and survival. Dapper1 (Dpr1), as a Dishevelled interactor, has been suggested to modulate Wnt signaling by promoting Dishevelled degradation. Here, we provide evidence that Dpr1 shuttles between the cytoplasm and the nucleus. Although overexpressed Dpr1 was mainly found in the cytoplasm, endogenous Dpr1 were localized over the cell and Wnt1 induced its nuclear export. Treatment with leptomycin B induced nuclear accumulation of both endogenous and overexpressed Dpr1, suggesting that Dpr1 shuttles between the cytoplasma and the nucleus. We further identified the nuclear localization signal and the nuclear export signal within Dpr1. Using reporter assay and in vivo zebrafish embryo assay, we demonstrated that the forced nuclear localization of Dpr1 possessed the ability to antagonize Wnt signaling. Dpr1 interacted withβ-catenin and LEF1 and disrupted their complex formation. Furthermore, Dpr1 could associate with HDAC1 and enhance the LEF1-HDAC1 interaction. Together, our findings suggest that Dpr1 negatively modulates the basal activity of Wnt/β-catenin signaling in the nucleus by keeping LEF1 in the repressive state. Thus, Dpr1 controls Wnt/β-catenin signaling in both the cytoplasm and the nucleus.
引文
[1] Cadigan K M, Nusse R. Wnt signaling: a common theme in animal development. Genes Dev, 1997, 11(24):3286-3305.
[2] Wodarz A, Nusse R. Mechanisms of Wnt signaling in development. Annu Rev Cell Dev Biol, 1998, 14:59-88.
[3] Sokol S. A role for Wnts in morpho-genesis and tissue polarity. Nat Cell Biol, 2000, 2(7):E124-125.
[4] Logan C Y, Nusse R. The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol, 2004, 20:781-810.
[5] Reya T, Clevers H. Wnt signalling in stem cells and cancer. Nature, 2005, 434(7035):843-850.
[6] Nusse R. Wnt signaling in disease and in development. Cell Res, 2005, 15(1):28-32.
[7] Clevers H. Wnt/beta-catenin signaling in development and disease. Cell, 2006, 127(3):469-480.
[8] Fuerer C, Nusse R, Ten Berge D. Wnt signalling in development and disease. Max Delbruck Center for Molecular Medicine meeting on Wnt signaling in Development and Disease. EMBO Rep, 2008, 9(2):134-138.
[9] Korinek V, Barker N, Morin P J, et al. Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC-/- colon carcinoma. Science, 1997, 275(5307):1784-1787.
[10] Morin P J, Sparks A B, Korinek V, et al. Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science, 1997, 275(5307):1787-1790.
[11] Bienz M, Clevers H. Linking colorectal cancer to Wnt signaling. Cell, 2000, 103(2):311-320.
[12] Barker N, Clevers H. Catenins, Wnt signaling and cancer. Bioessays, 2000, 22(11):961-965.
[13] Polakis P. Wnt signaling and cancer. Genes Dev, 2000, 14(15):1837-1851.
[14] Cheyette B N, Waxman J S, Miller J R, et al. Dapper, a Dishevelled-associated antagonist of beta-catenin and JNK signaling, is required for notochord formation. Dev Cell, 2002, 2(4):449-461.
[15] Gloy J, Hikasa H, Sokol S Y. Frodo interacts with Dishevelled to transduce Wnt signals. Nat Cell Biol, 2002, 4(5):351-357.
[16] Waxman J S, Hocking A M, Stoick C L, et al. Zebrafish Dapper1 and Dapper2 play distinct roles in Wnt-mediated developmental processes. Development, 2004, 131(23):5909-5921.
[17] Zhang L, Zhou H, Su Y, et al. Zebrafish Dpr2 inhibits mesoderm induction by promoting degradation of nodal receptors. Science, 2004, 306(5693):114-117.
[18] Yau T O, Chan C Y, Chan K L, et al. HDPR1, a novel inhibitor of the WNT/beta-catenin signaling, is frequently downregulated in hepatocellular carcinoma: involvement of methylation-mediated gene silencing. Oncogene, 2005, 24(9):1607-1614.
[19] Katoh M. Identification and characterization of human DAPPER1 and DAPPER2 genes in silico. Int J Oncol, 2003, 22(4):907-913.
[20] Porfiri E, Rubinfeld B, Albert I, et al. Induction of a beta-catenin-LEF-1 complex by wnt-1 and transforming mutants of beta-catenin. Oncogene, 1997, 15(23):2833-2839.
[21] He T C, Sparks A B, Rago C, et al. Identification of c-MYC as a target of the APC pathway. Science, 1998, 281(5382):1509-1512.
[22] Shtutman M, Zhurinsky J, Simcha I, et al. The cyclin D1 gene is a target of the beta-catenin/LEF-1 pathway. Proc Natl Acad Sci U S A, 1999, 96(10):5522-5527.
[23] Nusse R, Varmus H E. Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell, 1982, 31(1):99-109.
[24] Nusse R, Varmus H E. Wnt genes. Cell, 1992, 69(7):1073-1087.
[25] Nusse R, Brown A, Papkoff J, et al. A new nomenclature for int-1 and related genes: the Wnt gene family. Cell, 1991, 64(2):231.
[26] McMahon A P, Moon R T. Ectopic expression of the proto-oncogene int-1 in Xenopus embryos leads to duplication of the embryonic axis. Cell, 1989, 58(6):1075-1084.
[27] Dominguez I, Itoh K, Sokol S Y. Role of glycogen synthase kinase 3 beta as a negative regulator of dorsoventral axis formation in Xenopus embryos. Proc Natl Acad Sci U S A, 1995, 92(18):8498-8502.
[28] Guger K A, Gumbiner B M. beta-Catenin has Wnt-like activity and mimics the Nieuwkoop signaling center in Xenopus dorsal-ventral patterning. Dev Biol, 1995, 172(1):115-125.
[29] He X, Saint-Jeannet J P, Woodgett J R, et al. Glycogen synthase kinase-3 and dorsoventral patterning in Xenopus embryos. Nature, 1995, 374(6523):617-622.
[30] Kinzler K W, Nilbert M C, Su L K, et al. Identification of FAP locus genes from chromosome 5q21. Science, 1991, 253(5020):661-665.
[31] Nishisho I, Nakamura Y, Miyoshi Y, et al. Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science, 1991, 253(5020):665-669.
[32] Rubinfeld B, Souza B, Albert I, et al. Association of the APC gene product with beta-catenin. Science, 1993, 262(5140):1731-1734.
[33] Hulsken J, Birchmeier W, Behrens J. E-cadherin and APC compete for the interaction with beta-catenin and the cytoskeleton. J Cell Biol, 1994, 127(6 Pt 2):2061-2069.
[34] Su L K, Vogelstein B, Kinzler K W. Association of the APC tumor suppressor protein with catenins. Science, 1993, 262(5140):1734-1737.
[35] Mikels A J, Nusse R. Wnts as ligands: processing, secretion and reception. Oncogene, 2006, 25(57):7461-7468.
[36] Wang Y, Macke J P, Abella B S, et al. A large family of putative transmembrane receptors homologous to the product of the Drosophila tissue polarity gene frizzled. J Biol Chem, 1996, 271(8):4468-4476.
[37] Bhanot P, Brink M, Samos C H, et al. A new member of the frizzled family from Drosophila functions as a Wingless receptor. Nature, 1996, 382(6588):225-230.
[38] Gordon M D, Nusse R. Wnt signaling: multiple pathways, multiple receptors, and multiple transcription factors. J Biol Chem, 2006, 281(32):22429-22433.
[39] Habas R, Dawid I B. Dishevelled and Wnt signaling: is the nucleus the final frontier? J Biol, 2005, 4(1):2.
[40] Moon R T. Wnt/beta-catenin pathway. Sci STKE, 2005, 2005(271):cm1.
[41] Habas R, Kato Y, He X. Wnt/Frizzled activation of Rho regulates vertebrate gastrulation and requires a novel Formin homology protein Daam1. Cell, 2001, 107(7):843-854.
[42] Kuhl M, Sheldahl L C, Park M, et al. The Wnt/Ca2+ pathway: a new vertebrate Wnt signaling pathway takes shape. Trends Genet, 2000, 16(7):279-283.
[43] He X, Semenov M, Tamai K, et al. LDL receptor-related proteins 5 and 6 in Wnt/beta-catenin signaling: arrows point the way. Development, 2004, 131(8):1663-1677.
[44] Ikeda S, Kishida S, Yamamoto H, et al. Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK-3beta and beta-catenin and promotes GSK-3beta-dependent phosphorylation of beta-catenin. EMBO J, 1998, 17(5):1371-1384.
[45] Kishida S, Yamamoto H, Ikeda S, et al. Axin, a negative regulator of the wnt signaling pathway, directly interacts with adenomatous polyposis coli and regulates the stabilization of beta-catenin. J Biol Chem, 1998, 273(18):10823-10826.
[46] Nakamura T, Hamada F, Ishidate T, et al. Axin, an inhibitor of the Wnt signalling pathway, interacts with beta-catenin, GSK-3beta and APC and reduces the beta-catenin level. Genes Cells, 1998, 3(6):395-403.
[47] Aberle H, Bauer A, Stappert J, et al. beta-catenin is a target for the ubiquitin-proteasome pathway. EMBO J, 1997, 16(13):3797-3804.
[48] Hart M, Concordet J P, Lassot I, et al. The F-box protein beta-TrCP associates with phosphorylated beta-catenin and regulates its activity in the cell. Curr Biol, 1999, 9(4):207-210.
[49] Latres E, Chiaur D S, Pagano M. The human F box protein beta-Trcp associates with the Cul1/Skp1 complex and regulates the stability of beta-catenin. Oncogene, 1999, 18(4):849-854.
[50] Willert K, Shibamoto S, Nusse R. Wnt-induced dephosphorylation of axin releases beta-catenin from the axin complex. Genes Dev, 1999, 13(14):1768-1773.
[51] Molenaar M, van de Wetering M, Oosterwegel M, et al. XTcf-3 transcription factor mediates beta-catenin-induced axis formation in Xenopus embryos. Cell, 1996, 86(3):391-399.
[52] Behrens J, von Kries J P, Kuhl M, et al. Functional interaction of beta-catenin with the transcription factor LEF-1. Nature, 1996, 382(6592):638-642.
[53] Huber O, Korn R, McLaughlin J, et al. Nuclear localization of beta-catenin by interaction with transcription factor LEF-1. Mech Dev, 1996, 59(1):3-10.
[54] Veeman M T, Axelrod J D, Moon R T. A second canon. Functions and mechanisms of beta-catenin-independent Wnt signaling. Dev Cell, 2003, 5(3):367-377.
[55] Hsieh J C, Rattner A, Smallwood P M, et al. Biochemical characterization of Wnt-frizzled interactions using a soluble, biologically active vertebrate Wnt protein. Proc Natl Acad Sci U S A, 1999, 96(7):3546-3551.
[56] Boutros M, Mihaly J, Bouwmeester T, et al. Signaling specificity by Frizzled receptors in Drosophila. Science, 2000, 288(5472):1825-1828.
[57] Johnson M L, Harnish K, Nusse R, et al. LRP5 and Wnt signaling: a union made for bone. J Bone Miner Res, 2004, 19(11):1749-1757.
[58] Nusse R. Wnts and Hedgehogs: lipid-modified proteins and similarities in signaling mechanisms at the cell surface. Development, 2003, 130(22):5297-5305.
[59] Galli L M, Barnes T, Cheng T, et al. Differential inhibition of Wnt-3a by Sfrp-1, Sfrp-2, and Sfrp-3. Dev Dyn, 2006, 235(3):spc1.
[60] Itasaki N, Jones C M, Mercurio S, et al. Wise, a context-dependent activator and inhibitor of Wnt signalling. Development, 2003, 130(18):4295-4305.
[61] Guidato S, Itasaki N. Wise retained in the endoplasmic reticulum inhibits Wnt signaling by reducing cell surface LRP6. Dev Biol, 2007, 310(2):250-263.
[62] Glinka A, Wu W, Delius H, et al. Dickkopf-1 is a member of a new family of secreted proteins and functions in head induction. Nature, 1998, 391(6665):357-362.
[63] Mao B, Wu W, Li Y, et al. LDL-receptor-related protein 6 is a receptor for Dickkopf proteins. Nature, 2001, 411(6835):321-325.
[64] Mao B, Niehrs C. Kremen2 modulates Dickkopf2 activity during Wnt/LRP6 signaling. Gene, 2003, 302(1-2):179-183.
[65] Mao B, Wu W, Davidson G, et al. Kremen proteins are Dickkopf receptors that regulate Wnt/beta-catenin signalling. Nature, 2002, 417(6889):664-667.
[66] Amit S, Hatzubai A, Birman Y, et al. Axin-mediated CKI phosphorylation of beta-catenin at Ser 45: a molecular switch for the Wnt pathway. Genes Dev, 2002, 16(9):1066-1076.
[67] Liu C, Li Y, Semenov M, et al. Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell, 2002, 108(6):837-847.
[68] Yamamoto H, Kishida S, Kishida M, et al. Phosphorylation of axin, a Wnt signal negative regulator, by glycogen synthase kinase-3beta regulates its stability. J Biol Chem, 1999, 274(16):10681-10684.
[69] Rubinfeld B, Albert I, Porfiri E, et al. Binding of GSK3beta to the APC-beta-catenin complex and regulation of complex assembly. Science, 1996, 272(5264):1023-1026.
[70] Nelson W J, Nusse R. Convergence of Wnt, beta-catenin, and cadherin pathways. Science, 2004, 303(5663):1483-1487.
[71] Lee J S, Ishimoto A, Yanagawa S. Characterization of mouse dishevelled (Dvl) proteins in Wnt/Wingless signaling pathway. J Biol Chem, 1999, 274(30):21464-21470.
[72] Umbhauer M, Djiane A, Goisset C, et al. The C-terminal cytoplasmic Lys-thr-X-X-X-Trp motif in frizzled receptors mediates Wnt/beta-catenin signalling. EMBO J, 2000, 19(18):4944-4954.
[73] Axelrod J D, Miller J R, Shulman J M, et al. Differential recruitment of Dishevelled provides signaling specificity in the planar cell polarity and Wingless signaling pathways. Genes Dev, 1998, 12(16):2610-2622.
[74] Rothbacher U, Laurent M N, Deardorff M A, et al. Dishevelled phosphorylation, subcellular localization and multimerization regulate its role in early embryogenesis. EMBO J, 2000, 19(5):1010-1022.
[75] Chen W, ten Berge D, Brown J, et al. Dishevelled 2 recruits beta-arrestin 2 to mediate Wnt5A-stimulated endocytosis of Frizzled 4. Science, 2003, 301(5638):1391-1394.
[76] Wong H C, Bourdelas A, Krauss A, et al. Direct binding of the PDZ domain of Dishevelled to a conserved internal sequence in the C-terminal region of Frizzled. Mol Cell, 2003, 12(5):1251-1260.
[77] Axelrod J D. Unipolar membrane association of Dishevelled mediates Frizzled planar cell polarity signaling. Genes Dev, 2001, 15(10):1182-1187.
[78] Cliffe A, Hamada F, Bienz M. A role of Dishevelled in relocating Axin to the plasma membrane during wingless signaling. Curr Biol, 2003, 13(11):960-966.
[79] Strutt D. Frizzled signalling and cell polarisation in Drosophila and vertebrates. Development, 2003, 130(19):4501-4513.
[80] Boutros M, Mlodzik M. Dishevelled: at the crossroads of divergent intracellular signaling pathways. Mech Dev, 1999, 83(1-2):27-37.
[81] Adler P N. Planar signaling and morphogenesis in Drosophila. Dev Cell, 2002, 2(5):525-535.
[82] Kikuchi A. Roles of Axin in the Wnt signalling pathway. Cell Signal, 1999, 11(11):777-788.
[83] Luo W, Lin S C. Axin: a master scaffold for multiple signaling pathways. Neurosignals, 2004, 13(3):99-113.
[84] Zeng L, Fagotto F, Zhang T, et al. The mouse Fused locus encodes Axin, an inhibitor of the Wnt signaling pathway that regulates embryonic axis formation. Cell, 1997, 90(1):181-192.
[85] Mao J, Wang J, Liu B, et al. Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathway. Mol Cell, 2001, 7(4):801-809.
[86] Tolwinski N S, Wehrli M, Rives A, et al. Wg/Wnt signal can be transmitted through arrow/LRP5,6 and Axin independently of Zw3/Gsk3beta activity. Dev Cell, 2003, 4(3):407-418.
[87] Tamai K, Zeng X, Liu C, et al. A mechanism for Wnt coreceptor activation. Mol Cell, 2004, 13(1):149-156.
[88] Zeng X, Tamai K, Doble B, et al. A dual-kinase mechanism for Wnt co-receptor phosphorylation and activation. Nature, 2005, 438(7069):873-877.
[89] Mi K, Dolan P J, Johnson G V. The low density lipoprotein receptor-related protein 6 interacts with glycogen synthase kinase 3 and attenuates activity. J Biol Chem, 2006, 281(8):4787-4794.
[90] Swiatek W, Kang H, Garcia B A, et al. Negative regulation of LRP6 function by casein kinase I epsilon phosphorylation. J Biol Chem, 2006, 281(18):12233-12241.
[91] Davidson G, Wu W, Shen J, et al. Casein kinase 1 gamma couples Wnt receptor activation to cytoplasmic signal transduction. Nature, 2005, 438(7069):867-872.
[92] Zeng X, Huang H, Tamai K, et al. Initiation of Wnt signaling: control of Wnt coreceptor Lrp6 phosphorylation/activation via frizzled, dishevelled and axin functions. Development, 2008, 135(2):367-375.
[93] Wolf J, Palmby T R, Gavard J, et al. Multiple PPPS/TP motifs act in a combinatorial fashion to transduce Wnt signaling through LRP6. FEBS Lett, 2008, 582(2):255-261.
[94] Bilic J, Huang Y L, Davidson G, et al. Wnt induces LRP6 signalosomes and promotes dishevelled-dependent LRP6 phosphorylation. Science, 2007, 316(5831):1619-1622.
[95] Baig-Lewis S, Peterson-Nedry W, Wehrli M. Wingless/Wnt signal transduction requires distinct initiation and amplification steps that both depend on Arrow/LRP. Dev Biol, 2007, 306(1):94-111.
[96] Li L, Yuan H, Weaver C D, et al. Axin and Frat1 interact with dvl and GSK, bridging Dvl to GSK in Wnt-mediated regulation of LEF-1. EMBO J, 1999, 18(15):4233-4240.
[97] Jonkers J, Korswagen H C, Acton D, et al. Activation of a novel proto-oncogene, Frat1, contributes to progression of mouse T-cell lymphomas. EMBO J, 1997, 16(3):441-450.
[98] Nathke I. Cytoskeleton out of the cupboard: colon cancer and cytoskeletal changes induced by loss of APC. Nat Rev Cancer, 2006, 6(12):967-974.
[99] Senda T, Shimomura A, Iizuka-Kogo A. Adenomatous polyposis coli (Apc) tumor suppressor gene as a multifunctional gene. Anat Sci Int, 2005, 80(3):121-131.
[100] Fodde R, Smits R, Clevers H. APC, signal transduction and genetic instability in colorectal cancer. Nat Rev Cancer, 2001, 1(1):55-67.
[101] Shitashige M, Hirohashi S, Yamada T. Wnt signaling inside the nucleus. Cancer Sci, 2008, 99(4):631-637.
[102] Willert K, Jones K A. Wnt signaling: is the party in the nucleus? Genes Dev, 2006, 20(11):1394-1404.
[103] Travis A, Amsterdam A, Belanger C, et al. LEF-1, a gene encoding a lymphoid-specific protein with an HMG domain, regulates T-cell receptor alpha enhancer function [corrected]. Genes Dev, 1991, 5(5):880-894.
[104] Arce L, Yokoyama N N, Waterman M L. Diversity of LEF/TCF action in development and disease. Oncogene, 2006, 25(57):7492-7504.
[105] Giese K, Cox J, Grosschedl R. The HMG domain of lymphoid enhancer factor 1 bends DNA and facilitates assembly of functional nucleoprotein structures. Cell, 1992, 69(1):185-195.
[106] Bienz M. TCF: transcriptional activator or repressor? Curr Opin Cell Biol, 1998, 10(3):366-372.
[107] Cavallo R A, Cox R T, Moline M M, et al. Drosophila Tcf and Groucho interact to repress Wingless signalling activity. Nature, 1998, 395(6702):604-608.
[108] Chen G, Fernandez J, Mische S, et al. A functional interaction between the histone deacetylase Rpd3 and the corepressor groucho in Drosophila development. Genes Dev, 1999, 13(17):2218-2230.
[109] Valenta T, Lukas J, Korinek V. HMG box transcription factor TCF-4's interaction with CtBP1 controls the expression of the Wnt target Axin2/Conductin in human embryonic kidney cells. Nucleic Acids Res, 2003, 31(9):2369-2380.
[110] Ishitani T, Ninomiya-Tsuji J, Nagai S, et al. The TAK1-NLK-MAPK-related pathway antagonizes signalling between beta-catenin and transcription factor TCF. Nature, 1999, 399(6738):798-802.
[111] Ishitani T, Ninomiya-Tsuji J, Matsumoto K. Regulation of lymphoid enhancer factor 1/T-cell factor by mitogen-activated protein kinase-related Nemo-like kinase-dependent phosphorylation in Wnt/beta-catenin signaling. Mol Cell Biol, 2003, 23(4):1379-1389.
[112] Lo M C, Gay F, Odom R, et al. Phosphorylation by the beta-catenin/MAPK complex promotes 14-3-3-mediated nuclear export of TCF/POP-1 in signal-responsive cells in C. elegans. Cell, 2004, 117(1):95-106.
[113] Hecht A, Vleminckx K, Stemmler M P, et al. The p300/CBP acetyltransferases function as transcriptional coactivators of beta-catenin in vertebrates. EMBO J, 2000, 19(8):1839-1850.
[114] Takemaru K I, Moon R T. The transcriptional coactivator CBP interacts with beta-catenin to activate gene expression. J Cell Biol, 2000, 149(2):249-254.
[115] Daniels D L, Weis W I. Beta-catenin directly displaces Groucho/TLE repressors from Tcf/Lef in Wnt-mediated transcription activation. Nat Struct Mol Biol, 2005, 12(4):364-371.
[116] Barker N, Hurlstone A, Musisi H, et al. The chromatin remodelling factor Brg-1 interacts with beta-catenin to promote target gene activation. EMBO J, 2001, 20(17):4935-4943.
[117] Kramps T, Peter O, Brunner E, et al. Wnt/wingless signaling requires BCL9/legless-mediated recruitment of pygopus to the nuclear beta-catenin-TCF complex. Cell, 2002, 109(1):47-60.
[118] Parker D S, Jemison J, Cadigan K M. Pygopus, a nuclear PHD-finger protein required for Wingless signaling in Drosophila. Development, 2002, 129(11):2565-2576.
[119] Takemaru K, Yamaguchi S, Lee Y S, et al. Chibby, a nuclear beta-catenin-associated antagonist of the Wnt/Wingless pathway. Nature, 2003, 422(6934):905-909.
[120] Tago K, Nakamura T, Nishita M, et al. Inhibition of Wnt signaling by ICAT, a novel beta-catenin-interacting protein. Genes Dev, 2000, 14(14):1741-1749.
[121] Graham T A, Clements W K, Kimelman D, et al. The crystal structure of the beta-catenin/ICAT complex reveals the inhibitory mechanism of ICAT. Mol Cell, 2002, 10(3):563-571.
[122] Zhang L, Gao X, Wen J, et al. Dapper 1 antagonizes Wnt signaling by promoting dishevelled degradation. J Biol Chem, 2006, 281(13):8607-8612.
[123] Su Y, Zhang L, Gao X, et al. The evolutionally conserved activity of Dapper2 in antagonizing TGF-beta signaling. FASEB J, 2007, 21(3):682-690.
[124] Fisher D A, Kivimae S, Hoshino J, et al. Three Dact gene family members are expressed during embryonic development and in the adult brains of mice. Dev Dyn, 2006, 235(9):2620-2630.
[125]高霞,陈旭煌,陈晔光. Dapper在胚胎发育和信号调控中的作用.《生命科学》, 2007,5:471-476.
[126] Hikasa H, Sokol S Y. The involvement of Frodo in TCF-dependent signaling and neural tissue development. Development, 2004, 131(19):4725-4734.
[127] Brott B K, Sokol S Y. A vertebrate homolog of the cell cycle regulator Dbf4 is an inhibitor of Wnt signaling required for heart development. Dev Cell, 2005, 8(5):703-715.
[128] Park J I, Ji H, Jun S, et al. Frodo links Dishevelled to the p120-catenin/Kaiso pathway: distinct catenin subfamilies promote Wnt signals. Dev Cell, 2006, 11(5):683-695.
[129] Grote P, Schaeuble K, Ferrando-May E. Commuting (to) suicide: an update on nucleocytoplasmic transport in apoptosis. Arch Biochem Biophys, 2007, 462(2):156-161.
[130] Hart G W, Housley M P, Slawson C. Cycling of O-linked beta-N-acetylglucosamine on nucleocytoplasmic proteins. Nature, 2007, 446(7139):1017-1022.
[131] Truant R, Atwal R S, Burtnik A. Nucleocytoplasmic trafficking and transcription effects of huntingtin in Huntington's disease. Prog Neurobiol, 2007, 83(4):211-227.
[132] Ferrando-May E. Nucleocytoplasmic transport in apoptosis. Cell Death Differ, 2005, 12(10):1263-1276.
[133] Akimoto Y, Hart G W, Hirano H, et al. O-GlcNAc modification of nucleocytoplasmic proteins and diabetes. Med Mol Morphol, 2005, 38(2):84-91.
[134] Smith J M, Koopman P A. The ins and outs of transcriptional control: nucleocytoplasmic shuttling in development and disease. Trends Genet, 2004, 20(1):4-8.
[135] Xu L, Massague J. Nucleocytoplasmic shuttling of signal transducers. Nat Rev Mol Cell Biol, 2004, 5(3):209-219.
[136] Cartwright P, Helin K. Nucleocytoplasmic shuttling of transcription factors. Cell Mol Life Sci, 2000, 57(8-9):1193-1206.
[137] Pante N, Kann M. Nuclear pore complex is able to transport macromolecules with diameters of about 39 nm. Mol Biol Cell, 2002, 13(2):425-434.
[138] Fried H, Kutay U. Nucleocytoplasmic transport: taking an inventory. Cell Mol Life Sci, 2003, 60(8):1659-1688.
[139] Rout M P, Wente S R. Pores for thought: nuclear pore complex proteins. Trends Cell Biol, 1994, 4(10):357-365.
[140] Rout M P, Aitchison J D, Suprapto A, et al. The yeast nuclear pore complex: composition, architecture, and transport mechanism. J Cell Biol, 2000, 148(4):635-651.
[141] Cronshaw J M, Krutchinsky A N, Zhang W, et al. Proteomic analysis of the mammalian nuclear pore complex. J Cell Biol, 2002, 158(5):915-927.
[142] Joiner W J, Tang M D, Wang L Y, et al. Formation of intermediate-conductance calcium-activated potassium channels by interaction of Slack and Slo subunits. Nat Neurosci, 1998, 1(6):462-469.
[143] Tran E J, Wente S R. Dynamic nuclear pore complexes: life on the edge. Cell, 2006, 125(6):1041-1053.
[144] Shulga N, Goldfarb D S. Binding dynamics of structural nucleoporins govern nuclear pore complex permeability and may mediate channel gating. Mol Cell Biol, 2003, 23(2):534-542.
[145] Pemberton L F, Paschal B M. Mechanisms of receptor-mediated nuclear import and nuclear export. Traffic, 2005, 6(3):187-198.
[146] Weis K. Regulating access to the genome: nucleocytoplasmic transport throughout the cell cycle. Cell, 2003, 112(4):441-451.
[147] Goldfarb D S, Corbett A H, Mason D A, et al. Importin alpha: a multipurpose nuclear-transport receptor. Trends Cell Biol, 2004, 14(9):505-514.
[148] Jans D A, Xiao C Y, Lam M H. Nuclear targeting signal recognition: a key control point in nuclear transport? Bioessays, 2000, 22(6):532-544.
[149] Fornerod M, Ohno M, Yoshida M, et al. CRM1 is an export receptor for leucine-rich nuclear export signals. Cell, 1997, 90(6):1051-1060.
[150] Fukuda M, Asano S, Nakamura T, et al. CRM1 is responsible for intracellular transport mediated by the nuclear export signal. Nature, 1997, 390(6657):308-311.
[151] Kudo N, Matsumori N, Taoka H, et al. Leptomycin B inactivates CRM1/exportin 1 by covalent modification at a cysteine residue in the central conserved region. Proc Natl Acad Sci U S A, 1999, 96(16):9112-9117.
[152] Gorlich D, Kutay U. Transport between the cell nucleus and the cytoplasm. Annu Rev Cell Dev Biol, 1999, 15:607-660.
[153] Terry L J, Shows E B, Wente S R. Crossing the nuclear envelope: hierarchical regulation of nucleocytoplasmic transport. Science, 2007, 318(5855):1412-1416.
[154] Nigg E A. Nucleocytoplasmic transport: signals, mechanisms and regulation. Nature, 1997, 386(6627):779-787.
[155] Wente S R. Gatekeepers of the nucleus. Science, 2000, 288(5470):1374-1377.
[156] Fagotto F, Gluck U, Gumbiner B M. Nuclear localization signal-independent and importin/karyopherin-independent nuclear import of beta-catenin. Curr Biol, 1998, 8(4):181-190.
[157] Poon I K, Jans D A. Regulation of nuclear transport: central role in development and transformation? Traffic, 2005, 6(3):173-186.
[158] Rosin-Arbesfeld R, Townsley F, Bienz M. The APC tumour suppressor has a nuclear export function. Nature, 2000, 406(6799):1009-1012.
[159] Henderson B R. Nuclear-cytoplasmic shuttling of APC regulates beta-catenin subcellular localization and turnover. Nat Cell Biol, 2000, 2(9):653-660.
[160] Hamada F, Bienz M. The APC tumor suppressor binds to C-terminal binding protein to divert nuclear beta-catenin from TCF. Dev Cell, 2004, 7(5):677-685.
[161] Sierra J, Yoshida T, Joazeiro C A, et al. The APC tumor suppressor counteracts beta-catenin activation and H3K4 methylation at Wnt target genes. Genes Dev, 2006, 20(5):586-600.
[162] Cong F, Varmus H. Nuclear-cytoplasmic shuttling of Axin regulates subcellular localization of beta-catenin. Proc Natl Acad Sci U S A, 2004, 101(9):2882-2887.
[163] Wiechens N, Heinle K, Englmeier L, et al. Nucleo-cytoplasmic shuttling of Axin, a negative regulator of the Wnt-beta-catenin Pathway. J Biol Chem, 2004, 279(7):5263-5267.
[164] Bijur G N, Jope R S. Proapoptotic stimuli induce nuclear accumulation of glycogen synthase kinase-3 beta. J Biol Chem, 2001, 276(40):37436-37442.
[165] Franca-Koh J, Yeo M, Fraser E, et al. The regulation of glycogen synthase kinase-3 nuclear export by Frat/GBP. J Biol Chem, 2002, 277(46):43844-43848.
[166] Meares G P, Jope R S. Resolution of the nuclear localization mechanism of glycogen synthase kinase-3: functional effects in apoptosis. J Biol Chem, 2007, 282(23):16989-17001.
[167] Itoh K, Brott B K, Bae G U, et al. Nuclear localization is required for Dishevelled function in Wnt/beta-catenin signaling. J Biol, 2005, 4(1):3.
[168] Gan X Q, Wang J Y, Xi Y, et al. Nuclear Dvl, c-Jun, beta-catenin, and TCF form a complex leading to stabilization of beta-catenin-TCF interaction. J Cell Biol, 2008, 180(6):1087-1100.
[169] Wen W, Meinkoth J L, Tsien R Y, et al. Identification of a signal for rapid export of proteins from the nucleus. Cell, 1995, 82(3):463-473.
[170] Kalderon D, Richardson W D, Markham A F, et al. Sequence requirements for nuclear location of simian virus 40 large-T antigen. Nature, 1984, 311(5981):33-38.
[171] Robbins J, Dilworth S M, Laskey R A, et al. Two interdependent basic domains in nucleoplasmin nuclear targeting sequence: identification of a class of bipartite nuclear targeting sequence. Cell, 1991, 64(3):615-623.
[172] Lekven A C, Thorpe C J, Waxman J S, et al. Zebrafish wnt8 encodes two wnt8 proteins on a bicistronic transcript and is required for mesoderm and neurectoderm patterning. Dev Cell, 2001, 1(1):103-114.
[173] Roose J, Molenaar M, Peterson J, et al. The Xenopus Wnt effector XTcf-3 interacts with Groucho-related transcriptional repressors. Nature, 1998, 395(6702):608-612.
[174] Levanon D, Goldstein R E, Bernstein Y, et al. Transcriptional repression by AML1 and LEF-1 is mediated by the TLE/Groucho corepressors. Proc Natl Acad Sci U S A, 1998, 95(20):11590-11595.
[175] Billin A N, Thirlwell H, Ayer D E. Beta-catenin-histone deacetylase interactions regulate the transition of LEF1 from a transcriptional repressor to an activator. Mol Cell Biol, 2000, 20(18):6882-6890.
[2] Wodarz A, Nusse R. Mechanisms of Wnt signaling in development. Annu Rev Cell Dev Biol, 1998, 14:59-88.
[3] Sokol S. A role for Wnts in morpho-genesis and tissue polarity. Nat Cell Biol, 2000, 2(7):E124-125.
[4] Logan C Y, Nusse R. The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol, 2004, 20:781-810.
[5] Reya T, Clevers H. Wnt signalling in stem cells and cancer. Nature, 2005, 434(7035):843-850.
[6] Nusse R. Wnt signaling in disease and in development. Cell Res, 2005, 15(1):28-32.
[7] Clevers H. Wnt/beta-catenin signaling in development and disease. Cell, 2006, 127(3):469-480.
[8] Fuerer C, Nusse R, Ten Berge D. Wnt signalling in development and disease. Max Delbruck Center for Molecular Medicine meeting on Wnt signaling in Development and Disease. EMBO Rep, 2008, 9(2):134-138.
[9] Korinek V, Barker N, Morin P J, et al. Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC-/- colon carcinoma. Science, 1997, 275(5307):1784-1787.
[10] Morin P J, Sparks A B, Korinek V, et al. Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science, 1997, 275(5307):1787-1790.
[11] Bienz M, Clevers H. Linking colorectal cancer to Wnt signaling. Cell, 2000, 103(2):311-320.
[12] Barker N, Clevers H. Catenins, Wnt signaling and cancer. Bioessays, 2000, 22(11):961-965.
[13] Polakis P. Wnt signaling and cancer. Genes Dev, 2000, 14(15):1837-1851.
[14] Cheyette B N, Waxman J S, Miller J R, et al. Dapper, a Dishevelled-associated antagonist of beta-catenin and JNK signaling, is required for notochord formation. Dev Cell, 2002, 2(4):449-461.
[15] Gloy J, Hikasa H, Sokol S Y. Frodo interacts with Dishevelled to transduce Wnt signals. Nat Cell Biol, 2002, 4(5):351-357.
[16] Waxman J S, Hocking A M, Stoick C L, et al. Zebrafish Dapper1 and Dapper2 play distinct roles in Wnt-mediated developmental processes. Development, 2004, 131(23):5909-5921.
[17] Zhang L, Zhou H, Su Y, et al. Zebrafish Dpr2 inhibits mesoderm induction by promoting degradation of nodal receptors. Science, 2004, 306(5693):114-117.
[18] Yau T O, Chan C Y, Chan K L, et al. HDPR1, a novel inhibitor of the WNT/beta-catenin signaling, is frequently downregulated in hepatocellular carcinoma: involvement of methylation-mediated gene silencing. Oncogene, 2005, 24(9):1607-1614.
[19] Katoh M. Identification and characterization of human DAPPER1 and DAPPER2 genes in silico. Int J Oncol, 2003, 22(4):907-913.
[20] Porfiri E, Rubinfeld B, Albert I, et al. Induction of a beta-catenin-LEF-1 complex by wnt-1 and transforming mutants of beta-catenin. Oncogene, 1997, 15(23):2833-2839.
[21] He T C, Sparks A B, Rago C, et al. Identification of c-MYC as a target of the APC pathway. Science, 1998, 281(5382):1509-1512.
[22] Shtutman M, Zhurinsky J, Simcha I, et al. The cyclin D1 gene is a target of the beta-catenin/LEF-1 pathway. Proc Natl Acad Sci U S A, 1999, 96(10):5522-5527.
[23] Nusse R, Varmus H E. Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell, 1982, 31(1):99-109.
[24] Nusse R, Varmus H E. Wnt genes. Cell, 1992, 69(7):1073-1087.
[25] Nusse R, Brown A, Papkoff J, et al. A new nomenclature for int-1 and related genes: the Wnt gene family. Cell, 1991, 64(2):231.
[26] McMahon A P, Moon R T. Ectopic expression of the proto-oncogene int-1 in Xenopus embryos leads to duplication of the embryonic axis. Cell, 1989, 58(6):1075-1084.
[27] Dominguez I, Itoh K, Sokol S Y. Role of glycogen synthase kinase 3 beta as a negative regulator of dorsoventral axis formation in Xenopus embryos. Proc Natl Acad Sci U S A, 1995, 92(18):8498-8502.
[28] Guger K A, Gumbiner B M. beta-Catenin has Wnt-like activity and mimics the Nieuwkoop signaling center in Xenopus dorsal-ventral patterning. Dev Biol, 1995, 172(1):115-125.
[29] He X, Saint-Jeannet J P, Woodgett J R, et al. Glycogen synthase kinase-3 and dorsoventral patterning in Xenopus embryos. Nature, 1995, 374(6523):617-622.
[30] Kinzler K W, Nilbert M C, Su L K, et al. Identification of FAP locus genes from chromosome 5q21. Science, 1991, 253(5020):661-665.
[31] Nishisho I, Nakamura Y, Miyoshi Y, et al. Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science, 1991, 253(5020):665-669.
[32] Rubinfeld B, Souza B, Albert I, et al. Association of the APC gene product with beta-catenin. Science, 1993, 262(5140):1731-1734.
[33] Hulsken J, Birchmeier W, Behrens J. E-cadherin and APC compete for the interaction with beta-catenin and the cytoskeleton. J Cell Biol, 1994, 127(6 Pt 2):2061-2069.
[34] Su L K, Vogelstein B, Kinzler K W. Association of the APC tumor suppressor protein with catenins. Science, 1993, 262(5140):1734-1737.
[35] Mikels A J, Nusse R. Wnts as ligands: processing, secretion and reception. Oncogene, 2006, 25(57):7461-7468.
[36] Wang Y, Macke J P, Abella B S, et al. A large family of putative transmembrane receptors homologous to the product of the Drosophila tissue polarity gene frizzled. J Biol Chem, 1996, 271(8):4468-4476.
[37] Bhanot P, Brink M, Samos C H, et al. A new member of the frizzled family from Drosophila functions as a Wingless receptor. Nature, 1996, 382(6588):225-230.
[38] Gordon M D, Nusse R. Wnt signaling: multiple pathways, multiple receptors, and multiple transcription factors. J Biol Chem, 2006, 281(32):22429-22433.
[39] Habas R, Dawid I B. Dishevelled and Wnt signaling: is the nucleus the final frontier? J Biol, 2005, 4(1):2.
[40] Moon R T. Wnt/beta-catenin pathway. Sci STKE, 2005, 2005(271):cm1.
[41] Habas R, Kato Y, He X. Wnt/Frizzled activation of Rho regulates vertebrate gastrulation and requires a novel Formin homology protein Daam1. Cell, 2001, 107(7):843-854.
[42] Kuhl M, Sheldahl L C, Park M, et al. The Wnt/Ca2+ pathway: a new vertebrate Wnt signaling pathway takes shape. Trends Genet, 2000, 16(7):279-283.
[43] He X, Semenov M, Tamai K, et al. LDL receptor-related proteins 5 and 6 in Wnt/beta-catenin signaling: arrows point the way. Development, 2004, 131(8):1663-1677.
[44] Ikeda S, Kishida S, Yamamoto H, et al. Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK-3beta and beta-catenin and promotes GSK-3beta-dependent phosphorylation of beta-catenin. EMBO J, 1998, 17(5):1371-1384.
[45] Kishida S, Yamamoto H, Ikeda S, et al. Axin, a negative regulator of the wnt signaling pathway, directly interacts with adenomatous polyposis coli and regulates the stabilization of beta-catenin. J Biol Chem, 1998, 273(18):10823-10826.
[46] Nakamura T, Hamada F, Ishidate T, et al. Axin, an inhibitor of the Wnt signalling pathway, interacts with beta-catenin, GSK-3beta and APC and reduces the beta-catenin level. Genes Cells, 1998, 3(6):395-403.
[47] Aberle H, Bauer A, Stappert J, et al. beta-catenin is a target for the ubiquitin-proteasome pathway. EMBO J, 1997, 16(13):3797-3804.
[48] Hart M, Concordet J P, Lassot I, et al. The F-box protein beta-TrCP associates with phosphorylated beta-catenin and regulates its activity in the cell. Curr Biol, 1999, 9(4):207-210.
[49] Latres E, Chiaur D S, Pagano M. The human F box protein beta-Trcp associates with the Cul1/Skp1 complex and regulates the stability of beta-catenin. Oncogene, 1999, 18(4):849-854.
[50] Willert K, Shibamoto S, Nusse R. Wnt-induced dephosphorylation of axin releases beta-catenin from the axin complex. Genes Dev, 1999, 13(14):1768-1773.
[51] Molenaar M, van de Wetering M, Oosterwegel M, et al. XTcf-3 transcription factor mediates beta-catenin-induced axis formation in Xenopus embryos. Cell, 1996, 86(3):391-399.
[52] Behrens J, von Kries J P, Kuhl M, et al. Functional interaction of beta-catenin with the transcription factor LEF-1. Nature, 1996, 382(6592):638-642.
[53] Huber O, Korn R, McLaughlin J, et al. Nuclear localization of beta-catenin by interaction with transcription factor LEF-1. Mech Dev, 1996, 59(1):3-10.
[54] Veeman M T, Axelrod J D, Moon R T. A second canon. Functions and mechanisms of beta-catenin-independent Wnt signaling. Dev Cell, 2003, 5(3):367-377.
[55] Hsieh J C, Rattner A, Smallwood P M, et al. Biochemical characterization of Wnt-frizzled interactions using a soluble, biologically active vertebrate Wnt protein. Proc Natl Acad Sci U S A, 1999, 96(7):3546-3551.
[56] Boutros M, Mihaly J, Bouwmeester T, et al. Signaling specificity by Frizzled receptors in Drosophila. Science, 2000, 288(5472):1825-1828.
[57] Johnson M L, Harnish K, Nusse R, et al. LRP5 and Wnt signaling: a union made for bone. J Bone Miner Res, 2004, 19(11):1749-1757.
[58] Nusse R. Wnts and Hedgehogs: lipid-modified proteins and similarities in signaling mechanisms at the cell surface. Development, 2003, 130(22):5297-5305.
[59] Galli L M, Barnes T, Cheng T, et al. Differential inhibition of Wnt-3a by Sfrp-1, Sfrp-2, and Sfrp-3. Dev Dyn, 2006, 235(3):spc1.
[60] Itasaki N, Jones C M, Mercurio S, et al. Wise, a context-dependent activator and inhibitor of Wnt signalling. Development, 2003, 130(18):4295-4305.
[61] Guidato S, Itasaki N. Wise retained in the endoplasmic reticulum inhibits Wnt signaling by reducing cell surface LRP6. Dev Biol, 2007, 310(2):250-263.
[62] Glinka A, Wu W, Delius H, et al. Dickkopf-1 is a member of a new family of secreted proteins and functions in head induction. Nature, 1998, 391(6665):357-362.
[63] Mao B, Wu W, Li Y, et al. LDL-receptor-related protein 6 is a receptor for Dickkopf proteins. Nature, 2001, 411(6835):321-325.
[64] Mao B, Niehrs C. Kremen2 modulates Dickkopf2 activity during Wnt/LRP6 signaling. Gene, 2003, 302(1-2):179-183.
[65] Mao B, Wu W, Davidson G, et al. Kremen proteins are Dickkopf receptors that regulate Wnt/beta-catenin signalling. Nature, 2002, 417(6889):664-667.
[66] Amit S, Hatzubai A, Birman Y, et al. Axin-mediated CKI phosphorylation of beta-catenin at Ser 45: a molecular switch for the Wnt pathway. Genes Dev, 2002, 16(9):1066-1076.
[67] Liu C, Li Y, Semenov M, et al. Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell, 2002, 108(6):837-847.
[68] Yamamoto H, Kishida S, Kishida M, et al. Phosphorylation of axin, a Wnt signal negative regulator, by glycogen synthase kinase-3beta regulates its stability. J Biol Chem, 1999, 274(16):10681-10684.
[69] Rubinfeld B, Albert I, Porfiri E, et al. Binding of GSK3beta to the APC-beta-catenin complex and regulation of complex assembly. Science, 1996, 272(5264):1023-1026.
[70] Nelson W J, Nusse R. Convergence of Wnt, beta-catenin, and cadherin pathways. Science, 2004, 303(5663):1483-1487.
[71] Lee J S, Ishimoto A, Yanagawa S. Characterization of mouse dishevelled (Dvl) proteins in Wnt/Wingless signaling pathway. J Biol Chem, 1999, 274(30):21464-21470.
[72] Umbhauer M, Djiane A, Goisset C, et al. The C-terminal cytoplasmic Lys-thr-X-X-X-Trp motif in frizzled receptors mediates Wnt/beta-catenin signalling. EMBO J, 2000, 19(18):4944-4954.
[73] Axelrod J D, Miller J R, Shulman J M, et al. Differential recruitment of Dishevelled provides signaling specificity in the planar cell polarity and Wingless signaling pathways. Genes Dev, 1998, 12(16):2610-2622.
[74] Rothbacher U, Laurent M N, Deardorff M A, et al. Dishevelled phosphorylation, subcellular localization and multimerization regulate its role in early embryogenesis. EMBO J, 2000, 19(5):1010-1022.
[75] Chen W, ten Berge D, Brown J, et al. Dishevelled 2 recruits beta-arrestin 2 to mediate Wnt5A-stimulated endocytosis of Frizzled 4. Science, 2003, 301(5638):1391-1394.
[76] Wong H C, Bourdelas A, Krauss A, et al. Direct binding of the PDZ domain of Dishevelled to a conserved internal sequence in the C-terminal region of Frizzled. Mol Cell, 2003, 12(5):1251-1260.
[77] Axelrod J D. Unipolar membrane association of Dishevelled mediates Frizzled planar cell polarity signaling. Genes Dev, 2001, 15(10):1182-1187.
[78] Cliffe A, Hamada F, Bienz M. A role of Dishevelled in relocating Axin to the plasma membrane during wingless signaling. Curr Biol, 2003, 13(11):960-966.
[79] Strutt D. Frizzled signalling and cell polarisation in Drosophila and vertebrates. Development, 2003, 130(19):4501-4513.
[80] Boutros M, Mlodzik M. Dishevelled: at the crossroads of divergent intracellular signaling pathways. Mech Dev, 1999, 83(1-2):27-37.
[81] Adler P N. Planar signaling and morphogenesis in Drosophila. Dev Cell, 2002, 2(5):525-535.
[82] Kikuchi A. Roles of Axin in the Wnt signalling pathway. Cell Signal, 1999, 11(11):777-788.
[83] Luo W, Lin S C. Axin: a master scaffold for multiple signaling pathways. Neurosignals, 2004, 13(3):99-113.
[84] Zeng L, Fagotto F, Zhang T, et al. The mouse Fused locus encodes Axin, an inhibitor of the Wnt signaling pathway that regulates embryonic axis formation. Cell, 1997, 90(1):181-192.
[85] Mao J, Wang J, Liu B, et al. Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathway. Mol Cell, 2001, 7(4):801-809.
[86] Tolwinski N S, Wehrli M, Rives A, et al. Wg/Wnt signal can be transmitted through arrow/LRP5,6 and Axin independently of Zw3/Gsk3beta activity. Dev Cell, 2003, 4(3):407-418.
[87] Tamai K, Zeng X, Liu C, et al. A mechanism for Wnt coreceptor activation. Mol Cell, 2004, 13(1):149-156.
[88] Zeng X, Tamai K, Doble B, et al. A dual-kinase mechanism for Wnt co-receptor phosphorylation and activation. Nature, 2005, 438(7069):873-877.
[89] Mi K, Dolan P J, Johnson G V. The low density lipoprotein receptor-related protein 6 interacts with glycogen synthase kinase 3 and attenuates activity. J Biol Chem, 2006, 281(8):4787-4794.
[90] Swiatek W, Kang H, Garcia B A, et al. Negative regulation of LRP6 function by casein kinase I epsilon phosphorylation. J Biol Chem, 2006, 281(18):12233-12241.
[91] Davidson G, Wu W, Shen J, et al. Casein kinase 1 gamma couples Wnt receptor activation to cytoplasmic signal transduction. Nature, 2005, 438(7069):867-872.
[92] Zeng X, Huang H, Tamai K, et al. Initiation of Wnt signaling: control of Wnt coreceptor Lrp6 phosphorylation/activation via frizzled, dishevelled and axin functions. Development, 2008, 135(2):367-375.
[93] Wolf J, Palmby T R, Gavard J, et al. Multiple PPPS/TP motifs act in a combinatorial fashion to transduce Wnt signaling through LRP6. FEBS Lett, 2008, 582(2):255-261.
[94] Bilic J, Huang Y L, Davidson G, et al. Wnt induces LRP6 signalosomes and promotes dishevelled-dependent LRP6 phosphorylation. Science, 2007, 316(5831):1619-1622.
[95] Baig-Lewis S, Peterson-Nedry W, Wehrli M. Wingless/Wnt signal transduction requires distinct initiation and amplification steps that both depend on Arrow/LRP. Dev Biol, 2007, 306(1):94-111.
[96] Li L, Yuan H, Weaver C D, et al. Axin and Frat1 interact with dvl and GSK, bridging Dvl to GSK in Wnt-mediated regulation of LEF-1. EMBO J, 1999, 18(15):4233-4240.
[97] Jonkers J, Korswagen H C, Acton D, et al. Activation of a novel proto-oncogene, Frat1, contributes to progression of mouse T-cell lymphomas. EMBO J, 1997, 16(3):441-450.
[98] Nathke I. Cytoskeleton out of the cupboard: colon cancer and cytoskeletal changes induced by loss of APC. Nat Rev Cancer, 2006, 6(12):967-974.
[99] Senda T, Shimomura A, Iizuka-Kogo A. Adenomatous polyposis coli (Apc) tumor suppressor gene as a multifunctional gene. Anat Sci Int, 2005, 80(3):121-131.
[100] Fodde R, Smits R, Clevers H. APC, signal transduction and genetic instability in colorectal cancer. Nat Rev Cancer, 2001, 1(1):55-67.
[101] Shitashige M, Hirohashi S, Yamada T. Wnt signaling inside the nucleus. Cancer Sci, 2008, 99(4):631-637.
[102] Willert K, Jones K A. Wnt signaling: is the party in the nucleus? Genes Dev, 2006, 20(11):1394-1404.
[103] Travis A, Amsterdam A, Belanger C, et al. LEF-1, a gene encoding a lymphoid-specific protein with an HMG domain, regulates T-cell receptor alpha enhancer function [corrected]. Genes Dev, 1991, 5(5):880-894.
[104] Arce L, Yokoyama N N, Waterman M L. Diversity of LEF/TCF action in development and disease. Oncogene, 2006, 25(57):7492-7504.
[105] Giese K, Cox J, Grosschedl R. The HMG domain of lymphoid enhancer factor 1 bends DNA and facilitates assembly of functional nucleoprotein structures. Cell, 1992, 69(1):185-195.
[106] Bienz M. TCF: transcriptional activator or repressor? Curr Opin Cell Biol, 1998, 10(3):366-372.
[107] Cavallo R A, Cox R T, Moline M M, et al. Drosophila Tcf and Groucho interact to repress Wingless signalling activity. Nature, 1998, 395(6702):604-608.
[108] Chen G, Fernandez J, Mische S, et al. A functional interaction between the histone deacetylase Rpd3 and the corepressor groucho in Drosophila development. Genes Dev, 1999, 13(17):2218-2230.
[109] Valenta T, Lukas J, Korinek V. HMG box transcription factor TCF-4's interaction with CtBP1 controls the expression of the Wnt target Axin2/Conductin in human embryonic kidney cells. Nucleic Acids Res, 2003, 31(9):2369-2380.
[110] Ishitani T, Ninomiya-Tsuji J, Nagai S, et al. The TAK1-NLK-MAPK-related pathway antagonizes signalling between beta-catenin and transcription factor TCF. Nature, 1999, 399(6738):798-802.
[111] Ishitani T, Ninomiya-Tsuji J, Matsumoto K. Regulation of lymphoid enhancer factor 1/T-cell factor by mitogen-activated protein kinase-related Nemo-like kinase-dependent phosphorylation in Wnt/beta-catenin signaling. Mol Cell Biol, 2003, 23(4):1379-1389.
[112] Lo M C, Gay F, Odom R, et al. Phosphorylation by the beta-catenin/MAPK complex promotes 14-3-3-mediated nuclear export of TCF/POP-1 in signal-responsive cells in C. elegans. Cell, 2004, 117(1):95-106.
[113] Hecht A, Vleminckx K, Stemmler M P, et al. The p300/CBP acetyltransferases function as transcriptional coactivators of beta-catenin in vertebrates. EMBO J, 2000, 19(8):1839-1850.
[114] Takemaru K I, Moon R T. The transcriptional coactivator CBP interacts with beta-catenin to activate gene expression. J Cell Biol, 2000, 149(2):249-254.
[115] Daniels D L, Weis W I. Beta-catenin directly displaces Groucho/TLE repressors from Tcf/Lef in Wnt-mediated transcription activation. Nat Struct Mol Biol, 2005, 12(4):364-371.
[116] Barker N, Hurlstone A, Musisi H, et al. The chromatin remodelling factor Brg-1 interacts with beta-catenin to promote target gene activation. EMBO J, 2001, 20(17):4935-4943.
[117] Kramps T, Peter O, Brunner E, et al. Wnt/wingless signaling requires BCL9/legless-mediated recruitment of pygopus to the nuclear beta-catenin-TCF complex. Cell, 2002, 109(1):47-60.
[118] Parker D S, Jemison J, Cadigan K M. Pygopus, a nuclear PHD-finger protein required for Wingless signaling in Drosophila. Development, 2002, 129(11):2565-2576.
[119] Takemaru K, Yamaguchi S, Lee Y S, et al. Chibby, a nuclear beta-catenin-associated antagonist of the Wnt/Wingless pathway. Nature, 2003, 422(6934):905-909.
[120] Tago K, Nakamura T, Nishita M, et al. Inhibition of Wnt signaling by ICAT, a novel beta-catenin-interacting protein. Genes Dev, 2000, 14(14):1741-1749.
[121] Graham T A, Clements W K, Kimelman D, et al. The crystal structure of the beta-catenin/ICAT complex reveals the inhibitory mechanism of ICAT. Mol Cell, 2002, 10(3):563-571.
[122] Zhang L, Gao X, Wen J, et al. Dapper 1 antagonizes Wnt signaling by promoting dishevelled degradation. J Biol Chem, 2006, 281(13):8607-8612.
[123] Su Y, Zhang L, Gao X, et al. The evolutionally conserved activity of Dapper2 in antagonizing TGF-beta signaling. FASEB J, 2007, 21(3):682-690.
[124] Fisher D A, Kivimae S, Hoshino J, et al. Three Dact gene family members are expressed during embryonic development and in the adult brains of mice. Dev Dyn, 2006, 235(9):2620-2630.
[125]高霞,陈旭煌,陈晔光. Dapper在胚胎发育和信号调控中的作用.《生命科学》, 2007,5:471-476.
[126] Hikasa H, Sokol S Y. The involvement of Frodo in TCF-dependent signaling and neural tissue development. Development, 2004, 131(19):4725-4734.
[127] Brott B K, Sokol S Y. A vertebrate homolog of the cell cycle regulator Dbf4 is an inhibitor of Wnt signaling required for heart development. Dev Cell, 2005, 8(5):703-715.
[128] Park J I, Ji H, Jun S, et al. Frodo links Dishevelled to the p120-catenin/Kaiso pathway: distinct catenin subfamilies promote Wnt signals. Dev Cell, 2006, 11(5):683-695.
[129] Grote P, Schaeuble K, Ferrando-May E. Commuting (to) suicide: an update on nucleocytoplasmic transport in apoptosis. Arch Biochem Biophys, 2007, 462(2):156-161.
[130] Hart G W, Housley M P, Slawson C. Cycling of O-linked beta-N-acetylglucosamine on nucleocytoplasmic proteins. Nature, 2007, 446(7139):1017-1022.
[131] Truant R, Atwal R S, Burtnik A. Nucleocytoplasmic trafficking and transcription effects of huntingtin in Huntington's disease. Prog Neurobiol, 2007, 83(4):211-227.
[132] Ferrando-May E. Nucleocytoplasmic transport in apoptosis. Cell Death Differ, 2005, 12(10):1263-1276.
[133] Akimoto Y, Hart G W, Hirano H, et al. O-GlcNAc modification of nucleocytoplasmic proteins and diabetes. Med Mol Morphol, 2005, 38(2):84-91.
[134] Smith J M, Koopman P A. The ins and outs of transcriptional control: nucleocytoplasmic shuttling in development and disease. Trends Genet, 2004, 20(1):4-8.
[135] Xu L, Massague J. Nucleocytoplasmic shuttling of signal transducers. Nat Rev Mol Cell Biol, 2004, 5(3):209-219.
[136] Cartwright P, Helin K. Nucleocytoplasmic shuttling of transcription factors. Cell Mol Life Sci, 2000, 57(8-9):1193-1206.
[137] Pante N, Kann M. Nuclear pore complex is able to transport macromolecules with diameters of about 39 nm. Mol Biol Cell, 2002, 13(2):425-434.
[138] Fried H, Kutay U. Nucleocytoplasmic transport: taking an inventory. Cell Mol Life Sci, 2003, 60(8):1659-1688.
[139] Rout M P, Wente S R. Pores for thought: nuclear pore complex proteins. Trends Cell Biol, 1994, 4(10):357-365.
[140] Rout M P, Aitchison J D, Suprapto A, et al. The yeast nuclear pore complex: composition, architecture, and transport mechanism. J Cell Biol, 2000, 148(4):635-651.
[141] Cronshaw J M, Krutchinsky A N, Zhang W, et al. Proteomic analysis of the mammalian nuclear pore complex. J Cell Biol, 2002, 158(5):915-927.
[142] Joiner W J, Tang M D, Wang L Y, et al. Formation of intermediate-conductance calcium-activated potassium channels by interaction of Slack and Slo subunits. Nat Neurosci, 1998, 1(6):462-469.
[143] Tran E J, Wente S R. Dynamic nuclear pore complexes: life on the edge. Cell, 2006, 125(6):1041-1053.
[144] Shulga N, Goldfarb D S. Binding dynamics of structural nucleoporins govern nuclear pore complex permeability and may mediate channel gating. Mol Cell Biol, 2003, 23(2):534-542.
[145] Pemberton L F, Paschal B M. Mechanisms of receptor-mediated nuclear import and nuclear export. Traffic, 2005, 6(3):187-198.
[146] Weis K. Regulating access to the genome: nucleocytoplasmic transport throughout the cell cycle. Cell, 2003, 112(4):441-451.
[147] Goldfarb D S, Corbett A H, Mason D A, et al. Importin alpha: a multipurpose nuclear-transport receptor. Trends Cell Biol, 2004, 14(9):505-514.
[148] Jans D A, Xiao C Y, Lam M H. Nuclear targeting signal recognition: a key control point in nuclear transport? Bioessays, 2000, 22(6):532-544.
[149] Fornerod M, Ohno M, Yoshida M, et al. CRM1 is an export receptor for leucine-rich nuclear export signals. Cell, 1997, 90(6):1051-1060.
[150] Fukuda M, Asano S, Nakamura T, et al. CRM1 is responsible for intracellular transport mediated by the nuclear export signal. Nature, 1997, 390(6657):308-311.
[151] Kudo N, Matsumori N, Taoka H, et al. Leptomycin B inactivates CRM1/exportin 1 by covalent modification at a cysteine residue in the central conserved region. Proc Natl Acad Sci U S A, 1999, 96(16):9112-9117.
[152] Gorlich D, Kutay U. Transport between the cell nucleus and the cytoplasm. Annu Rev Cell Dev Biol, 1999, 15:607-660.
[153] Terry L J, Shows E B, Wente S R. Crossing the nuclear envelope: hierarchical regulation of nucleocytoplasmic transport. Science, 2007, 318(5855):1412-1416.
[154] Nigg E A. Nucleocytoplasmic transport: signals, mechanisms and regulation. Nature, 1997, 386(6627):779-787.
[155] Wente S R. Gatekeepers of the nucleus. Science, 2000, 288(5470):1374-1377.
[156] Fagotto F, Gluck U, Gumbiner B M. Nuclear localization signal-independent and importin/karyopherin-independent nuclear import of beta-catenin. Curr Biol, 1998, 8(4):181-190.
[157] Poon I K, Jans D A. Regulation of nuclear transport: central role in development and transformation? Traffic, 2005, 6(3):173-186.
[158] Rosin-Arbesfeld R, Townsley F, Bienz M. The APC tumour suppressor has a nuclear export function. Nature, 2000, 406(6799):1009-1012.
[159] Henderson B R. Nuclear-cytoplasmic shuttling of APC regulates beta-catenin subcellular localization and turnover. Nat Cell Biol, 2000, 2(9):653-660.
[160] Hamada F, Bienz M. The APC tumor suppressor binds to C-terminal binding protein to divert nuclear beta-catenin from TCF. Dev Cell, 2004, 7(5):677-685.
[161] Sierra J, Yoshida T, Joazeiro C A, et al. The APC tumor suppressor counteracts beta-catenin activation and H3K4 methylation at Wnt target genes. Genes Dev, 2006, 20(5):586-600.
[162] Cong F, Varmus H. Nuclear-cytoplasmic shuttling of Axin regulates subcellular localization of beta-catenin. Proc Natl Acad Sci U S A, 2004, 101(9):2882-2887.
[163] Wiechens N, Heinle K, Englmeier L, et al. Nucleo-cytoplasmic shuttling of Axin, a negative regulator of the Wnt-beta-catenin Pathway. J Biol Chem, 2004, 279(7):5263-5267.
[164] Bijur G N, Jope R S. Proapoptotic stimuli induce nuclear accumulation of glycogen synthase kinase-3 beta. J Biol Chem, 2001, 276(40):37436-37442.
[165] Franca-Koh J, Yeo M, Fraser E, et al. The regulation of glycogen synthase kinase-3 nuclear export by Frat/GBP. J Biol Chem, 2002, 277(46):43844-43848.
[166] Meares G P, Jope R S. Resolution of the nuclear localization mechanism of glycogen synthase kinase-3: functional effects in apoptosis. J Biol Chem, 2007, 282(23):16989-17001.
[167] Itoh K, Brott B K, Bae G U, et al. Nuclear localization is required for Dishevelled function in Wnt/beta-catenin signaling. J Biol, 2005, 4(1):3.
[168] Gan X Q, Wang J Y, Xi Y, et al. Nuclear Dvl, c-Jun, beta-catenin, and TCF form a complex leading to stabilization of beta-catenin-TCF interaction. J Cell Biol, 2008, 180(6):1087-1100.
[169] Wen W, Meinkoth J L, Tsien R Y, et al. Identification of a signal for rapid export of proteins from the nucleus. Cell, 1995, 82(3):463-473.
[170] Kalderon D, Richardson W D, Markham A F, et al. Sequence requirements for nuclear location of simian virus 40 large-T antigen. Nature, 1984, 311(5981):33-38.
[171] Robbins J, Dilworth S M, Laskey R A, et al. Two interdependent basic domains in nucleoplasmin nuclear targeting sequence: identification of a class of bipartite nuclear targeting sequence. Cell, 1991, 64(3):615-623.
[172] Lekven A C, Thorpe C J, Waxman J S, et al. Zebrafish wnt8 encodes two wnt8 proteins on a bicistronic transcript and is required for mesoderm and neurectoderm patterning. Dev Cell, 2001, 1(1):103-114.
[173] Roose J, Molenaar M, Peterson J, et al. The Xenopus Wnt effector XTcf-3 interacts with Groucho-related transcriptional repressors. Nature, 1998, 395(6702):608-612.
[174] Levanon D, Goldstein R E, Bernstein Y, et al. Transcriptional repression by AML1 and LEF-1 is mediated by the TLE/Groucho corepressors. Proc Natl Acad Sci U S A, 1998, 95(20):11590-11595.
[175] Billin A N, Thirlwell H, Ayer D E. Beta-catenin-histone deacetylase interactions regulate the transition of LEF1 from a transcriptional repressor to an activator. Mol Cell Biol, 2000, 20(18):6882-6890.