Rethinking WNT signaling
Abstract
Recent research on the WNT signaling pathway warrants a reassessment of the basic mechanism that transmits signal from the membrane-bound receptor to the nucleus. This article incorporates these findings into a revised model for pathway activation. We propose that the control of Axin stability, rather than the control of ZW3 phosphorylation of the Armadillo protein, is the key step in signaling. Axin degradation is controlled by a stabilizing effect of ZW3-dependent phosphorylation, and a destabilizing effect of active Arrow. Removing Axin enables Armadillo to accumulate and re-localize to the nucleus. We argue that nuclear localization of Armadillo is required for transcriptional pathway activity. Finally, we speculate on the effects this revision will have on the major questions facing the WNT field of research.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
GSK-3β controls cell survival through regulation of β-catenin, and inhibition of Akt suppresses the Wnt pathway by activation of GSK-3β and degradation of β-catenin.
“At the same time, GSK-3β also controls cell survival through regulation of β-catenin, 1 of the key molecules in Wnt signaling (11), and inhibition of Akt suppresses the Wnt pathway by activation of GSK-3β and degradation of ß-catenin (51).”
From Anabolic effect of plant brassinosteroid (2011) · cites this paper as [11]
Cites
1 retracted
Chan, S.-K., & Struhl, G. (2002) · Cell · doi:10.1016/s0092-8674(02)01037-1 · Cited by 58 · see citing works
RetractedPolakis, P. (2000) · Genes & Development · doi:10.1101/gad.14.15.1837 · Cited by 3,183 · see citing works
MECHANISMS OF WNT SIGNALING IN DEVELOPMENT
Wodarz, A., & Nusse, R. (1998) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.14.1.59 · Cited by 2,017 · see citing works
Nusse, R., & VARMUS, H. E. (1982) · Cell · doi:10.1016/0092-8674(82)90409-3 · Cited by 1,864 · see citing works
Jho, E., Zhang, T., Domon–Dell, C., Joo, C., Freund, J., & Costantini, F. D. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.4.1172-1183.2002 · Cited by 1,683 · see citing works
Veeman, M. T., Axelrod, J. D., & Moon, R. T. (2003) · Developmental Cell · doi:10.1016/s1534-5807(03)00266-1 · Cited by 1,359 · see citing works
Wetering, M. L. V. D., Cavallo, R. A., Dooijes, D., van Beest, M., van Es, J. V., Loureiro, J., Ypma, A., Hursh, D., Jones, T. L., Bejsovec, A., et al. (1997) · Cell · doi:10.1016/s0092-8674(00)81925-x · Cited by 1,347 · see citing works
LDL-receptor-related proteins in Wnt signal transduction
Tamai, K., Semënov, M. V., Kato, Y., Spokony, R. F., Liu, C., Katsuyama, Y., Hess, F. J., Saint‐Jeannet, J., & He, X. (2000) · Nature · doi:10.1038/35035117 · Cited by 1,334 · see citing works
Wnt Signaling in Oncogenesis and Embryogenesis--a Look Outside the Nucleus
Peifer, M., & Polakis, P. (2000) · Science · doi:10.1126/science.287.5458.1606 · Cited by 1,253 · see citing works
Lustig, B., Jerchow, B., Sachs, M., Weiler, S., Pietsch, T., Karsten, U., van de Wetering, M., Clevers, H., Schlag, P., Birchmeier, W., et al. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.4.1184-1193.2002 · Cited by 1,198 · see citing works
An LDL-receptor-related protein mediates Wnt signalling in mice
Pinson, K. I., Brennan, J., Monkley, S. J., Avery, B. J., & Skarnes, W. C. (2000) · Nature · doi:10.1038/35035124 · Cited by 1,086 · see citing works
arrow encodes an LDL-receptor-related protein essential for Wingless signalling
Wehrli, M., Dougan, S. T., Caldwell, K. A., O’Keefe, L. V., Schwartz, S. L., Vaizel-Ohayon, D., Schejter, E. D., Tomlinson, A., & DiNardo, S. (2000) · Nature · doi:10.1038/35035110 · Cited by 871 · see citing works
Mao, J., Wang, J., Liu, B., Pan, W., Farr, G. H., Flynn, C., Yuan, H., Takada, S., Kimelman, D., Li, L., et al. (2001) · Molecular Cell · doi:10.1016/s1097-2765(01)00224-6 · Cited by 839 · cited 1× · see citing works
“13 Mao, J. et al. (2001) Low-density lipoprotein receptor-related protein-5”
Drosophila Tcf and Groucho interact to repress Wingless signalling activity
Cavallo, R. A., Cox, R. T., Moline, M. M., Roose, J., Polevoy, G. A., Clevers, H., Peifer, M., & Bejsovec, A. (1998) · Nature · doi:10.1038/26982 · Cited by 730 · see citing works
The Roles of APC and Axin Derived from Experimental and Theoretical Analysis of the Wnt Pathway
Lee, E., Salic, A., Krüger, R., Heinrich, R., & Kirschner, M. W. (2003) · PLoS Biology · doi:10.1371/journal.pbio.0000010 · Cited by 708 · see citing works
Kramps, T., Peter, O., Brunner, E., Anthamatten, D., Froesch, B. A., Chatterjee, S., Murone, M., Züllig, S., & Basler, K. (2002) · Cell · doi:10.1016/s0092-8674(02)00679-7 · Cited by 562 · see citing works
Wong, H.-C., Bourdelas, A., Krauss, A., Lee, H., Shao, Y., Wu, D., Mlodzik, M., Shi, D., & Zheng, J. (2003) · Molecular Cell · doi:10.1016/s1097-2765(03)00427-1 · Cited by 531 · see citing works
Fagotto, F., Glück, U., & Gumbiner, B. M. (1998) · Current Biology · doi:10.1016/s0960-9822(98)70082-x · Cited by 434 · see citing works
Peifer, M. A., Sweeton, D., Casey, M. J., & Wieschaus, E. F. (1994) · Development · doi:10.1242/dev.120.2.369 · Cited by 426 · see citing works
Self-citationSiegfried, E., Chou, T.-B., & Perrimon, N. (1992) · Cell · doi:10.1016/s0092-8674(05)80065-0 · Cited by 423 · see citing works
Yamamoto, H., Kishida, S., Kishida, M., Ikeda, S., Takada, S., & Kikuchi, A. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.16.10681 · Cited by 364 · see citing works
Wnt-induced dephosphorylation of Axin releases beta -catenin from the Axin complexPreprint
Willert, K., Shibamoto, S., & Nusse, R. (1999) · Genes & Development · doi:10.1101/gad.13.14.1768 · Cited by 337 · see citing works
A Role of Dishevelled in Relocating Axin to the Plasma Membrane during Wingless Signaling
Cliffe, A., Hamada, F., & Bienz, M. (2003) · Current Biology · doi:10.1016/s0960-9822(03)00370-1 · Cited by 289 · see citing works
Riggleman, B., Wieschaus, E. F., & Schedl, P. D. (1989) · Genes & Development · doi:10.1101/gad.3.1.96 · Cited by 289 · see citing works
Self-citationA new nuclear component of the Wnt signalling pathway
Thompson, B. J., Townsley, F. M., Rosin‐Arbesfeld, R., Musisi, H., & Bienz, M. (2002) · Nature Cell Biology · doi:10.1038/ncb786 · Cited by 288 · see citing works
Wg/Wnt Signal Can Be Transmitted through Arrow/LRP5,6 and Axin Independently of Zw3/Gsk3β Activity
Tolwinski, N. S., Wehrli, M., Rives, A., Erdeniz, N., DiNardo, S., & Wieschaus, E. (2003) · Developmental Cell · doi:10.1016/s1534-5807(03)00063-7 · Cited by 286 · see citing works
Self-citationChibby, a nuclear β-catenin-associated antagonist of the Wnt/Wingless pathway
Takemaru, K., Yamaguchi, S., Lee, Y. S., Zhang, Y., Carthew, R. W., & Moon, R. T. (2003) · Nature · doi:10.1038/nature01570 · Cited by 274 · see citing works
Pygopus, a nuclear PHD-finger protein required for Wingless signaling inDrosophila
Parker, D. S., Jemison, J., & Cadigan, K. M. (2002) · Development · doi:10.1242/dev.129.11.2565 · Cited by 238 · see citing works
Regulation of Armadillo by a Drosophila APC Inhibits Neuronal Apoptosis during Retinal Development
Ahmed, Y. F., Hayashi, S., Levine, A. J., & Wieschaus, E. F. (1998) · Cell · doi:10.1016/s0092-8674(00)81461-0 · Cited by 220 · see citing works
Self-citationNegative Regulation of Wingless Signaling by D-Axin, a Drosophila Homolog of Axin
Hamada, F., Tomoyasu, Y., Takatsu, Y., Nakamura, M., Nagai, S.-I., Suzuki, A., Fujita, F., Shibuyà, H., Toyoshima, K., Ueno, N., et al. (1999) · Science · doi:10.1126/science.283.5408.1739 · Cited by 197 · see citing works
Armadillo/β-catenin signals in the nucleus – proof beyond a reasonable doubt?
Bienz, M., & Clevers, H. (2003) · Nature Cell Biology · doi:10.1038/ncb0303-179 · Cited by 137 · see citing works
A <i>Drosophila Axin</i> homolog, <i>Daxin</i>, inhibits Wnt signaling
Willert, K., Logan, C. Y., Arora, A., Fish, M., & Nusse, R. (1999) · Development · doi:10.1242/dev.126.18.4165 · Cited by 117 · see citing works
Armadillo nuclear import is regulated by cytoplasmic anchor Axin and nuclear anchor dTCF/Pan
Tolwinski, N. S., & Wieschaus, E. F. (2001) · Development · doi:10.1242/dev.128.11.2107 · Cited by 109 · see citing works
Self-citationJho, E., Lomvardas, S., & Costantini, F. D. (1999) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1999.1760 · Cited by 95 · see citing works
DrosophilaApc1 and Apc2 regulate Wingless transduction throughout development
Ahmed, Y. F., Nouri, A., & Wieschaus, E. F. (2002) · Development · doi:10.1242/dev.129.7.1751 · Cited by 93 · see citing works
Self-citationA Nuclear Function for Armadillo/β-Catenin
Tolwinski, N. S., & Wieschaus, E. F. (2004) · PLoS Biology · doi:10.1371/journal.pbio.0020095 · Cited by 92 · see citing works
Self-citationHe, X. (2003) · Developmental Cell · doi:10.1016/s1534-5807(03)00165-5 · Cited by 89 · see citing works
Membrane-tethered Drosophila Armadillo cannot transduce Wingless signal on its own
Cox, R. T., Pai, L., Miller, J. R., Oršulić, S., Stein, J., McCormick, C. A., Audeh, Y., Wang, W., Moon, R. T., & Peifer, M. A. (1999) · Development · doi:10.1242/dev.126.6.1327 · Cited by 55 · see citing works
Requirement for Pangolin/dTCF in Drosophila Wingless signaling
Schweizer, L., Nellen, D., & Basler, K. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1037533100 · Cited by 43 · see citing works
Getting legless with a Pygopus
Greaves, S. (2002) · Nature Cell Biology · doi:10.1038/ncb0502-e124 · Cited by 2 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
WNT and β-catenin signalling: diseases and therapies
Moon, R. T., Kohn, A. D., Ferrari, G. V. D., & Kaykas, A. (2004) · Nature Reviews Genetics · doi:10.1038/nrg1427 · Cited by 1,763 · see citing works
“A core set of proteins and an ever-growing list of proteins that modify their function have been identified in this way, as thoroughly reviewed elsewher”
BackgroundHelicobacter pylori and Gastric Cancer: Factors That Modulate Disease Risk
Wroblewski, L. E., Peek, R. M., & Wilson, K. T. (2010) · Clinical Microbiology Reviews · doi:10.1128/cmr.00011-10 · Cited by 1,455 · see citing works
“This complex targets -catenin for ubiquitination and subsequent degradation (309).”
BackgroundHelicobacter pylori: gastric cancer and beyond
Polk, D. B., & Peek, R. M. (2010) · Nature Reviews Cancer · doi:10.1038/nrc2857 · Cited by 1,158 · see citing works
Wnt Induces LRP6 Signalosomes and Promotes Dishevelled-Dependent LRP6 Phosphorylation
Bilić, J., Huang, Y., Davidson, G. R., Zimmermann, T., Cruciat, C., Bienz, M., & Niehrs, C. (2007) · Science · doi:10.1126/science.1137065 · Cited by 923 · see citing works
Casein kinase 1 γ couples Wnt receptor activation to cytoplasmic signal transduction
Davidson, G. R., Wu, W., Shen, J., Bilić, J., Fenger, U., Stannek, P., Glinka, A., & Niehrs, C. (2005) · Nature · doi:10.1038/nature04170 · Cited by 581 · see citing works
The developmental biology of Dishevelled: an enigmatic protein governing cell fate and cell polarity
Wallingford, J. B., & Habas, R. (2005) · Development · doi:10.1242/dev.02068 · Cited by 509 · see citing works
Wnt signaling: complexity at the surface
Cadigan, K. M., & Liu, Y. I. (2006) · Journal of Cell Science · doi:10.1242/jcs.02826 · Cited by 486 · see citing works
“-catenin/Arm nuclear localization, owing to loss of cytoplasmic tethering (Tolwinski and Wieschaus, 2001; Tolwinski and Wieschaus, 2004).”
BackgroundActivation of β-catenin by carcinogenic Helicobacter pylori
Franco, A. T., Israel, D. A., Washington, M. K., Krishna, U. S., Fox, J. G., Rogers, A. B., Neish, A. S., Collier-Hyams, L. S., Perez-Perez, G. I., Hatakeyama, M., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0504927102 · Cited by 479 · see citing works
Wnt-dependent Regulation of the E-cadherin Repressor Snail
Yook, J. I., Li, X., Ota, I., Fearon, E. R., & Weiss, S. J. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m413878200 · Cited by 443 · see citing works
Wnt/β-catenin signalling: from plasma membrane to nucleus
Kim, W., Kim, M., & Jho, E. (2013) · Biochemical Journal · doi:10.1042/bj20121284 · Cited by 310 · see citing works
Intrinsic disorder in scaffold proteins: Getting more from less
Cortese, M. S., Uversky, V. N., & Dunker, A. K. (2008) · Progress in Biophysics and Molecular Biology · doi:10.1016/j.pbiomolbio.2008.05.007 · Cited by 292 · see citing works
“…et al., 1998), the transforming growth factor β (TGF-β) (Furuhashi et al., 2001), the c-Jun NH2-terminal/stress-activated protein kinase (JNK) (Zhang et al., 1999) and the p53 signaling pathways (Luo and Lin, 2004; Rui et al., 2004; Salahshor and Woodgett, 2005; Tolwinski and Wieschaus, 2004).”
BackgroundWnt/Notch signalling and information processing during development
Hayward, P. C., Kalmár, T., & Arias, A. M. (2008) · Development · doi:10.1242/dev.000505 · Cited by 290 · see citing works
“The effector of Wnt signalling in the nucleus is -catenin (Tolwinski and Wieschaus, 2004a).”
BackgroundInfluentialThe canonical Wnt signalling pathway and its APC partner in colon cancer development
Schneikert, J., & Behrens, J. (2006) · Gut · doi:10.1136/gut.2006.093310 · Cited by 289 · see citing works
Yang, L., Lin, C., & Liu, Z.-R. (2006) · Cell · doi:10.1016/j.cell.2006.08.036 · Cited by 288 · see citing works
“It was shown that Axin functioned to anchor b-catenin in the cytoplasm (Tolwinski and Wieschaus, 2004).”
BackgroundThe WNT/Beta-catenin pathway in melanoma
Larue, L. (2006) · Frontiers in bioscience · doi:10.2741/1831 · Cited by 249 · see citing works
“Wnt proteins bind to target cells via two families of receptors: Frizzed (Fzd) and LDLreceptor-related proteins (13, 14).”
BackgroundThe links between axin and carcinogenesis
Salahshor, S., & Woodgett, J. R. (2005) · Journal of Clinical Pathology · doi:10.1136/jcp.2003.009506 · Cited by 250 · see citing works
Non-canonical Notch signaling: emerging role and mechanism
Andersen, P., Uosaki, H., Shenje, L. T., & Kwon, C. (2012) · Trends in Cell Biology · doi:10.1016/j.tcb.2012.02.003 · Cited by 238 · see citing works
Moon, R. T. (2005) · Science s STKE · doi:10.1126/stke.2712005cm1 · Cited by 220 · see citing works
Segmentation in vertebrates: clock and gradient finally joinedPreprint
Aulehla, A., & Herrmann, B. G. (2004) · Genes & Development · doi:10.1101/gad.1217404 · Cited by 212 · see citing works
Cselenyi, C. S., Jernigan, K. K., Tahinci, E., Thorne, C. A., Lee, L. A., & Lee, E. N. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0803025105 · Cited by 207 · see citing works
“As a result, LRP5/6mediated Axin degradation has been proposed to be a critical event in transduction of a Wnt signal (10).”
BackgroundDevelopment of dopaminergic neurons in the mammalian brain
Prakash, N., & Wurst, W. (2006) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-005-5387-6 · Cited by 207 · see citing works
Hayward, P., Brennan, K. R., Sanders, P., Balayo, T., DasGupta, R., Perrimon, N., & Arias, A. M. (2005) · Development · doi:10.1242/dev.01724 · Cited by 204 · see citing works
“While the central role of Armadillo/β-catenin is well established, the mechanism by which it is activated remains open to discussion (Giles et al., 2003; Tolwinski and Wieschaus, 2004b).”
BackgroundWnt–Notch signalling crosstalk in development and disease
Collu, G. M., Hidalgo‐Sastre, A., & Brennan, K. R. (2014) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-014-1644-x · Cited by 197 · see citing works
A Tale of Two Toxins: Helicobacter Pylori CagA and VacA Modulate Host Pathways that Impact Disease
Jones, K. R., Whitmire, J. M., & Merrell, D. S. (2010) · Frontiers in Microbiology · doi:10.3389/fmicb.2010.00115 · Cited by 190 · see citing works
“β-catenin has two distinct functions, it links cadherins with the actin cytoskeleton and is part of the WNT signaling pathway (Tolwinski and Wieschaus, 2004).”
Zhang, W., Zhao, Y., Tong, C., Wang, G., Wang, B., Jia, J., & Jiang, J. (2005) · Developmental Cell · doi:10.1016/j.devcel.2005.01.001 · Cited by 187 · see citing works
Brassinosteroids and plant function: some clues, more puzzles
Haubrick, L. L., & Assmann, S. M. (2006) · Plant Cell & Environment · doi:10.1111/j.1365-3040.2005.01481.x · Cited by 176 · see citing works
Wnt/Fz signaling and the cytoskeleton: potential roles in tumorigenesis
Lai, S.-L., Chien, A. J., & Moon, R. T. (2009) · Cell Research · doi:10.1038/cr.2009.41 · Cited by 158 · see citing works
Glycogen synthase kinase-3 in insulin and Wnt signalling: a double-edged sword?
Patel, S., Doble, B. W., & Woodgett, J. R. (2004) · Biochemical Society Transactions · doi:10.1042/bst0320803 · Cited by 153 · see citing works
Minireview: Transcriptional Regulation of Adrenocortical Development
Hammer, G. D., Parker, K. L., & Schimmer, B. P. (2004) · Endocrinology · doi:10.1210/en.2004-1385 · Cited by 143 · see citing works
“Wnt proteins are secreted glycoproteins that act via the frizzled receptor (FZD) family associated with the frizzled receptor coreceptor, low-density lipoprotein receptor-related protein-5 or -6 to initiate a canonical cascade of intracellular signals leading to -catenin accumulation in the nucleus and subsequent tran…”
BackgroundWroblewski, L. E., Piazuelo, M. B., Chaturvedi, R., Schumacher, M., Aihara, E., Feng, R., Noto, J. M., Delgado, A., Israel, D. A., Zavros, Y., et al. (2015) · Gut · doi:10.1136/gutjnl-2014-307650 · Cited by 143 · see citing works
PTK7/Otk interacts with Wnts and inhibits canonical Wnt signalling
Peradziryi, H., Kaplan, N., Podleschny, M., Liu, X., Wehner, P., Borchers, A., & Tolwinski, N. S. (2011) · The EMBO Journal · doi:10.1038/emboj.2011.236 · Cited by 135 · see citing works
“In the canonical pathway, Axin is brought to the membrane by Arr/LRP5/6 and this step is required to inactivate the destruction complex (Tolwinski et al, 2003; Tolwinski and Wieschaus, 2001, 2004).”
BackgroundSelf-citationThe canonical Wnt pathway in early mammalian embryogenesis and stem cell maintenance/differentiation
Wang, J., & Wynshaw-Boris, A. J. (2004) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2004.07.013 · Cited by 127 · see citing works
Mouse Axin and Axin2/Conductin Proteins Are Functionally Equivalent In Vivo
Chia, I. V., & Costantini, F. D. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.11.4371-4376.2005 · Cited by 121 · see citing works
“Axin is a central component of the canonical Wnt signal transduction machinery, serving as a scaffold for the -catenin destruction complex (23, 31, 36, 45, 52).”
BackgroundInfluentialBuchholz, M., Kestler, H. A., Holzmann, K., Ellenrieder, V., Schneiderhan, W., Siech, M., Adler, G., Bachem, M. G., & Gress, T. M. (2005) · Journal of Molecular Medicine · doi:10.1007/s00109-005-0680-2 · Cited by 122 · see citing works
“Wnt signalling through different pathways is a central regulatory mechanism in various developmental processes, including cell differentiation, cell polarity, cell migration and cell proliferation (for an overview, see [29, 30]).”
BackgroundCatalán, V., Gómez‐Ambrosi, J., Rodrı́guez, A., Pérez-Hernández, A. I., Gurbindo, J., Ramírez, B., Méndez-Giménez, L., Rotellar, F., Valentí, V., Moncada, R., et al. (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2014-1191 · Cited by 113 · see citing works
“The best characterized WNT pathway activates the nuclear functions of -catenin (39, 40).”
BackgroundTCFs and Wnt/β-catenin Signaling
Cadigan, K. M. (2012) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/b978-0-12-386499-4.00001-x · Cited by 106 · see citing works
Epigenetic silencing of AXIN2 in colorectal carcinoma with microsatellite instability
Koinuma, K., Yamashita, Y., Liu, W., Hatanaka, H., Kurashina, K., Wada, T., Takada, S., Kaneda, R., Choi, Y. L., Fujiwara, S.-I., et al. (2005) · Oncogene · doi:10.1038/sj.onc.1209009 · Cited by 106 · see citing works
“Oncogene Oncogene The isolated MSI-associated genes include AXIN2 and CTNNB1 (b-catenin), both of which encode key participants in the WNT signaling pathway (Tolwinski and Wieschaus, 2004).”
BackgroundWnt signal transduction and the formation of the myocardium
Eisenberg, L. M., & Eisenberg, C. A. (2006) · Developmental Biology · doi:10.1016/j.ydbio.2006.02.014 · Cited by 105 · see citing works
The role of the Hes1 crosstalk hub in Notch-Wnt interactions of the intestinal crypt
Kay, S. K., Harrington, H. A., Shepherd, S., Brennan, K. R., Dale, T. C., Osborne, J. M., Gavaghan, D. J., & Byrne, H. M. (2017) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1005400 · Cited by 116 · see citing works
“Model simulations [15,16] have led to suggestions that Axin might regulate crosstalk between Wnt and other pathways (e.”
β‐catenin as a potential key target for tumor suppression
Fu, Y., Zheng, S., An, N., Athanasopoulos, T., Popplewell, L. J., Liang, A., Li, K., Hu, C., & Zhu, Y. (2011) · International Journal of Cancer · doi:10.1002/ijc.26102 · Cited by 101 · see citing works
“that the degradation of Axin was critical for signal transduction.(38) However, this hypothesis is challenged by the fact that Wnt-induced stabilization of b-catenin in cultured mammalian cells occurs about 2 hr before decreased concentration of Axin is detectable.”
BackgroundMorphogens and synaptogenesis in Drosophila
Marqués, G. (2005) · Journal of Neurobiology · doi:10.1002/neu.20165 · Cited by 94 · see citing works
Kim, S., & Jho, E. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.137471 · Cited by 91 · see citing works
Caveolin-1–LRP6 Signaling Module Stimulates Aerobic Glycolysis in Prostate Cancer
Tahir, S. A., Yang, G., Goltsov, A. A., Song, K., Ren, C., Wang, J., Chang, W., & Thompson, T. C. (2013) · Cancer Research · doi:10.1158/0008-5472.can-12-3040 · Cited by 89 · see citing works
“This phosphorylation event activates LRP6 and promotes recruitment of Axin (18, 19), which results in stabilization of b-cat (13).”
Cha, B., Kim, W., Kim, Y., Hwang, B. N., Park, S. Y., Yoon, J., Park, W. S., Cho, J. W., Bedford, M. T., & Jho, E. (2011) · Oncogene · doi:10.1038/onc.2010.610 · Cited by 85 · see citing works
“As the level of b-catenin in the Axin complex is regulated, tight control of Axin expression is considered the key step in the transduction Oncogene of Wnt/b-catenin signaling (Tolwinski and Wieschaus, 2004; Bedford, 2007).”
BackgroundLavergne, E., Hendaoui, I., Coulouarn, C., Ribault, C., Leseur, J., Eliat, P., Mebarki, S., Corlu, A., Clément, B., & Musso, O. C. (2010) · Oncogene · doi:10.1038/onc.2010.432 · Cited by 79 · see citing works
“Therefore, although the major mechanism of regulation of β-catenin activity is phosphorylation, the Wnt pathway may use multiple ways to regulate the concentration of β-catenin (Salahshor and Woodgett, 2005; Tolwinski and Wieschaus, 2004).”
BackgroundKapsimali, M., Caneparo, L., Houart, C., & Wilson, S. W. (2004) · Development · doi:10.1242/dev.01453 · Cited by 76 · see citing works
“Altogether these results suggest that Axin1 may facilitate Nodal signalling in addition to its wellestablished role in antagonising Wnt signalling (Jones and Bejsovec, 2003; Tolwinski and Wieschaus, 2004).”
BackgroundTwo Sides of the Same Coin: Wnt Signaling in Neurodegeneration and Neuro-Oncology
Caricasole, A., Bakker, A. C., Copani, A., Nicoletti, F., Gaviraghi, G., & Terstappen, G. C. (2005) · Bioscience Reports · doi:10.1007/s10540-005-2893-6 · Cited by 76 · see citing works
“…and on its participation in ligand-dependent LRP binding and as a key scaffolding protein in the b-catenin degradation complex, it has been proposed that levels of Axin might be the rate-limiting step in the process, rather than b-catenin phosphorylation by GSK3b (Tolwinski and Wieschaus, 2004).”
BackgroundInfluentialWingless Signaling Induces Widespread Chromatin Remodeling of Target Loci
Parker, D. S., Ni, Y., Chang, J. L., Li, J., & Cadigan, K. M. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.01230-07 · Cited by 72 · see citing works
Lhx5 promotes forebrain development and activates transcription of secreted Wnt antagonists
Peng, G., & Westerfield, M. (2006) · Development · doi:10.1242/dev.02485 · Cited by 71 · see citing works
“The current view of Wnt signaling suggests that the docking of Axin1 to Lrp (the LDL receptor related protein) and the concomitant removal of Axin1 from the -catenin degradation complex is the crucial step in the activation of the Wnt signaling pathway (Logan and Nusse, 2004; Tolwinski and Wieschaus, 2004).”
BackgroundInfluentialAn Oncogenic Hub: β-Catenin as a Molecular Target for Cancer Therapeutics
Takemaru, K., Ohmitsu, M., & Li, F. Q. (2008) · Handbook of experimental pharmacology · doi:10.1007/978-3-540-72843-6_11 · Cited by 70 · see citing works
Gopal, U., Jayanthi, V., Devaraj, N., & Devaraj, H. (2007) · Molecular Carcinogenesis · doi:10.1002/mc.20311 · Cited by 68 · see citing works
Wei, Q., Zhao, Y., Yang, Z., Dong, Q., Dong, X.-J., Han, Y., Chen, Z., & Wang, E. (2008) · Lung Cancer · doi:10.1016/j.lungcan.2008.06.018 · Cited by 64 · see citing works
“This results in the cytoplasmic accumulation of -catenin, which then translocates into the nucleus, where it complexes with members of the TCF/LEF family of transcription factors and induces the transcription of Wnt-responsive genes [5—9].”
BackgroundThe role of the cysteine‐rich domain of Frizzled in Wingless‐Armadillo signaling
Povelones, M., & Nusse, R. (2005) · The EMBO Journal · doi:10.1038/sj.emboj.7600817 · Cited by 65 · see citing works
“In Drosophila, Wg signaling through Armadillo (Arm, Drosophila b-catenin) is required for patterning embryos (reviewed in Logan and Nusse, 2004; Tolwinski and Wieschaus, 2004; Bejsovec, 2005).”
BackgroundThe trimeric G protein Go inflicts a double impact on axin in the Wnt/frizzled signaling pathway
Egger‐Adam, D., & Katanaev, V. L. (2009) · Developmental Dynamics · doi:10.1002/dvdy.22060 · Cited by 60 · see citing works
“Additionally, not only localization but also abundance of the components of the Wnt pathway are known to change in cells with high levels of Fz activation as part of the feedback regulation (Tolwinski and Wieschaus, 2004; Itoh et al., 2005; Angers et al., 2006; Yokoyama et al., 2007; Jung et al., 2009).”
BackgroundTanaka, T., Gondo, S., Okabe, T., Ohe, K., Shirohzu, H., Morinaga, H., Nomura, M., Tani, K., Takayanagi, R., Nawata, H., et al. (2007) · Journal of Molecular Endocrinology · doi:10.1677/jme-07-0076 · Cited by 60 · see citing works
“Wnt proteins act via the frizzled receptor family to initiate a canonical cascade of intracellular signals leading to b-catenin accumulation in the nucleus and subsequent transactivation of downstream target genes (Tolwinski & Wieschaus 2004).”
BackgroundFujimuro, M., Liu, J., Zhu, J. K., Yokosawa, H., & Hayward, S. D. (2005) · Journal of Virology · doi:10.1128/jvi.79.16.10429-10441.2005 · Cited by 60 · see citing works
“The lower level of phosphorylation supported by CKI may reflect fewer CKI priming sites in LANA(1-340) than for MAPK or, alternatively, CKI priming may be underestimated.”
BackgroundMethodInfluentialvan Leeuwen, I. M. M., Byrne, H. M., Jensen, O. E., & King, J. R. (2007) · Journal of Theoretical Biology · doi:10.1016/j.jtbi.2007.01.019 · Cited by 59 · see citing works
Kalkman, H. O. (2008) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2008.11.002 · Cited by 59 · see citing works
“Depending on the degree of Wnt signaling this complex degrades either β-catenin or axin (Tolwinski & Wieschaus, 2004; Hay et al., 2005).”
Background"Targeted disruption of the epithelial-barrier by Helicobacter pylori"
Wroblewski, L. E., & Peek, R. M. (2011) · Cell Communication and Signaling · doi:10.1186/1478-811x-9-29 · Cited by 58 · see citing works
“This complex constitutively targets b-catenin for degradation by the ubiquitin-proteasome pathway [101].”
BackgroundKim, M. J., Chia, I. V., & Costantini, F. D. (2008) · The FASEB Journal · doi:10.1096/fj.08-113910 · Cited by 56 · see citing works
“Because the degradation of Axin may play an important role in the transmission of a Wnt signal (3, 12), it will be interesting in the future to determine whether the ubiquitination of Axin is altered by Wnt signaling and whether the SUMOylation of the C6 motif plays a regulatory role in this process.”
BackgroundSalim, T., Sand‐Dejmek, J., & Sjölander, A. (2013) · Experimental Cell Research · doi:10.1016/j.yexcr.2013.10.021 · Cited by 54 · see citing works
Popov, B. V., Serikov, V. B., Ns, P., Izusova, T. V., Gupta, N., & Matthay, M. A. (2007) · Tissue Engineering · doi:10.1089/ten.2007.0001 · Cited by 55 · see citing works
The inhibitory effects of Disabled-2 (Dab2) on Wnt signaling are mediated through Axin
Jiang, Y. Q., Prunier, C., & Howe, P. H. (2007) · Oncogene · doi:10.1038/sj.onc.1210829 · Cited by 54 · see citing works
“Recently, however, GSK3-independent regulation of Wnt signaling has been suggested (Tolwinski and Wieschaus, 2004) involving Dvl and the scaffolding protein Axin that binds APC, b-catenin, GSK3, casein kinase 1 and Dvl (Polakis, 2002).”
BackgroundMammalian Sex Determination and Gonad Development
Wilhelm, D., Yang, J. X., & Thomas, P. Q. (2013) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/b978-0-12-416021-7.00003-1 · Cited by 53 · see citing works
Lee, H. K., Kwak, H. Y., Hur, J., Kim, I. A., Yang, J., Park, M. W., Yu, J., & Jeong-Yu, S. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-1128 · Cited by 53 · see citing works
A multiple timescale analysis of a mathematical model of the Wnt/β-catenin signalling pathway
Mirams, G. R., Byrne, H. M., & King, J. R. (2010) · Journal of Mathematical Biology · doi:10.1007/s00285-009-0262-y · Cited by 53 · see citing works
“However, Lee et al. (2003) published a detailed ODE-based model which replicated experimental results extremely well and significantly changed the way in which the Wnt pathway was thought to operate (Tolwinski and Wieschaus 2004).”
BackgroundResultHämmerlein, A., Weiske, J., & Huber, O. (2005) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-005-4507-7 · Cited by 51 · see citing works
SP100 inhibits ETS1 activity in primary endothelial cells
Yordy, J. S., Moussa, O., Pei, H., Chaussabel, D., Li, R., & Watson, D. K. (2004) · Oncogene · doi:10.1038/sj.onc.1208245 · Cited by 51 · see citing works
Wnt/β-Catenin signaling acts at multiple developmental stages to promote mammalian cardiogenesis
Kwon, C., Cordes, K. R., & Srivastava, D. (2008) · Cell Cycle · doi:10.4161/cc.7.24.7189 · Cited by 51 · see citing works
Luo, W., Zou, H., Jin, L., Lin, S., Li, Q., Ye, Z., Rui, H., & Lin, S. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m412340200 · Cited by 49 · see citing works
The Roles of Intrinsic Disorder in Orchestrating the Wnt-Pathway
Xue, B., Dunker, A. K., & Uversky, V. N. (2012) · Journal of Biomolecular Structure and Dynamics · doi:10.1080/073911012010525024 · Cited by 49 · see citing works
O’Connor, P. M. J., Lapointe, T. K., Jackson, S. C., Beck, P. L., Jones, N. L., & Buret, A. G. (2011) · Infection and Immunity · doi:10.1128/iai.05109-11 · Cited by 46 · see citing works
“Activation of Wnt signaling induces a series of events that culminate in nuclear translocation of -catenin and binding of the lymphoid enhancer factor (LEF)/T cell factor (TCF) transcription factors to activate targeted transcription of genes involved in apoptosis, proliferation, and carcinogenesis, including MMP-7, c…”
BackgroundAnabolic effect of plant brassinosteroid
Esposito, D., Komarnytsky, S., Shapses, S., & Raskin, I. (2011) · The FASEB Journal · doi:10.1096/fj.11-181271 · Cited by 44 · see citing works
“At the same time, GSK-3 also controls cell survival through regulation of -catenin, 1 of the key molecules in Wnt signaling (11), and inhibition of Akt suppresses the Wnt pathway by activation of GSK-3 and degradation of ß-catenin (51).”
BackgroundMultiple PPPS/TP motifs act in a combinatorial fashion to transduce Wnt signaling through LRP6
Wolf, J., Palmby, T. R., Gavard, J., Williams, B. O., & Gutkind, J. S. (2007) · FEBS Letters · doi:10.1016/j.febslet.2007.12.013 · Cited by 44 · see citing works
Notch synergizes with axin to regulate the activity of armadillo in Drosophila
Hayward, P. C., Balayo, T., & Arias, A. M. (2006) · Developmental Dynamics · doi:10.1002/dvdy.20902 · Cited by 41 · see citing works
“…two functions, one as the scaffold for the phosphorylation of Armadillo/ - catenin (reviewed in Logan and Nusse, 2004) and a second one demonstrated in Drosophila embryos, in which it acts as an anchor that prevents the activity of Armadillo (Tolwinski et al., 2003; Tolwinski and Wieschaus, 2004b).”
BackgroundInfluentialSpatially defined Dsh–Lgl interaction contributes to directional tissue morphogenesis
Kaplan, N., & Tolwinski, N. S. (2010) · Journal of Cell Science · doi:10.1242/jcs.069898 · Cited by 42 · see citing works
“To accomplish this, we took dsh (M/Z) mutant embryos and introduced a stabilized Armadillo (Arm; catenin) transgene (serine 56 to alanine point mutant), which prevents the kinase-dependent degradation machinery from removing cytoplasmic Arm (Tolwinski and Wieschaus, 2004b).”
Self-citationHoffmans, R., & Basler, K. (2006) · Mechanisms of Development · doi:10.1016/j.mod.2006.09.006 · Cited by 38 · see citing works
A Comparative Perspective on Wnt/β-Catenin Signalling in Cell Fate Determination
Garcin, C. L., & Habib, S. J. (2017) · Results and problems in cell differentiation · doi:10.1007/978-3-319-53150-2_15 · Cited by 36 · see citing works
GSK3β affects apical–basal polarity and cell–cell adhesion by regulating aPKC levels
Colosimo, P. F., Liu, X., Kaplan, N., & Tolwinski, N. S. (2009) · Developmental Dynamics · doi:10.1002/dvdy.21963 · Cited by 34 · see citing works
Self-citationPovelones, M., Howes, R., Fish, M., & Nusse, R. (2005) · Genetics · doi:10.1534/genetics.105.045245 · Cited by 32 · see citing works
“As Arm accumulates in the cytoplasm and nucleus, it interacts with Pangolin (Pan), a transcription factor from the T-cell factor/lymphoid enhancer factor family to regulate target gene expression (reviewed in Logan and Nusse 2004; Tolwinski and Wieschaus 2004; Bejsovec 2005).”
BackgroundBuceta, J., Herranz, H., Canela‐Xandri, O., Reigada, R., Sagués, F., & Milán, M. (2007) · PLoS ONE · doi:10.1371/journal.pone.0000602 · Cited by 32 · see citing works
“The Wg signaling pathway is activated by controlling the levels and subcellular localization of the transcriptional coactivator Armadillo (Arm, known as ß-catenin in vertebrates; reviewed in [42]).”
BackgroundDescalzo, S. M., Tkocz, K., Balayo, T., & Arias, A. M. (2011) · Development · doi:10.1242/dev.061309 · Cited by 32 · see citing works
“In the current model of Wnt signalling, a complex assembled around Axin and Apc allows GSK3 (Shaggy) to phosphorylate Armadillo and target it for degradation.”
BackgroundInfluentialKennell, J. A., & Cadigan, K. M. (2009) · Advances in experimental medicine and biology · doi:10.1007/978-1-4419-1145-2_1 · Cited by 31 · see citing works
Negative feedback regulation of Wnt signaling by Gβγ-mediated reduction of Dishevelled
Jung, H., Kim, H. J., Lee, S. K., Kim, R., Kopachik, W. J., Han, J., & Jho, E. (2009) · Experimental & Molecular Medicine · doi:10.3858/emm.2009.41.10.076 · Cited by 31 · see citing works
“number of proteins to regulate Wnt/β-catenin signaling (Lee et al., 2003; Tolwinski and Wieschaus, 2004; Kikuchi et al., 2006).”
Ptk7 and Mcc, Unfancied Components in Non-Canonical Wnt Signaling and Cancer
Dunn, N. R., & Tolwinski, N. (2016) · Cancers · doi:10.3390/cancers8070068 · Cited by 34 · see citing works
“One such signal, involved in a variety of contexts, is known as the Wnt signaling pathway [1–5].”
BackgroundSelf-citationColorectal cancer through simulation and experiment
Kershaw, S. K., Byrne, H. M., Gavaghan, D. J., & Osborne, J. M. (2013) · IET Systems Biology · doi:10.1049/iet-syb.2012.0019 · Cited by 27 · see citing works
Mathematical modelling of Wnt/β-catenin signalling
Kofahl, B., & Wolf, J. (2010) · Biochemical Society Transactions · doi:10.1042/bst0381281 · Cited by 27 · see citing works
Guo, G., Kuai, D., Cai, S., Xue, N., Liu, Y., Hao, J.-H., Fan, Y., Ji, J., Mao, X., Liu, B., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0061206 · Cited by 26 · see citing works
“factor/lymphoid enhancer factor) family and activates the transcription of Wnt/b-catenin target genes, such as c-myc and cyclin D1, which function as oncogenes [31,32,33,34].”
BackgroundEpithelial Polarity: Interactions Between Junctions and Apical–Basal Machinery
Kaplan, N., Liu, X., & Tolwinski, N. S. (2009) · Genetics · doi:10.1534/genetics.109.108878 · Cited by 25 · see citing works
Self-citationHu, L., Kawamoto, E. M., Brietzke, E. M., Scavone, C., & Lafer, B. (2010) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2010.08.031 · Cited by 24 · see citing works
The expression profile of FRAT1 in human gliomas
Guo, G., Mao, X., Wang, P., Liu, B., Zhang, X., Jiang, X., Zhong, C., Huo, J., Ji, J., & Zhuo, Y. (2010) · Brain Research · doi:10.1016/j.brainres.2010.01.037 · Cited by 23 · see citing works
Guo, G., Liu, B., Zhong, C., Zhang, X., Mao, X., Wang, P., Jiang, X., Huo, J., Ji, J., Liu, X., et al. (2009) · Medical Oncology · doi:10.1007/s12032-009-9402-x · Cited by 22 · see citing works
“cyclin D1 [22–25].”
Himaya, S. W. A., Dewapriya, P., & Kim, S. (2013) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2013.03.020 · Cited by 21 · see citing works
Wnt Signaling in Sexual Dimorphism
Deshpande, G., Nouri, A., & Schedl, P. D. (2015) · Genetics · doi:10.1534/genetics.115.177857 · Cited by 21 · see citing works
Regulation of Stem Cell Self-Renewal and Oncogenesis by RNA-Binding Proteins.
Hattori, A., Buac, K., & Ito, T. (2016) · Advances in Experimental Medicine and Biology · doi:10.1007/978-3-319-29073-7_7 · Cited by 20 · see citing works
Evolution of the Cadherin–Catenin Complex
Hiroki, O. (2012) · Sub-cellular biochemistry/Subcellular biochemistry · doi:10.1007/978-94-007-4186-7_2 · Cited by 20 · see citing works
Chang, H. W., Nam, H. Y., Kim, H. J., Moon, S. Y., Kim, M. R., Lee, M., Kim, G. C., Kim, S. W., & Kim, S. Y. (2015) · Head & Neck · doi:10.1002/hed.24347 · Cited by 19 · see citing works
“Overexpression of Dvl-3 is associated with nuclear b-catenin accumulation and Wnt/b-catenin signaling activation.(23) We first confirmed active Wnt signaling in head and neck cancer cell lines by checking the expression of b-catenin and Dvl-3.”
BackgroundThe expression and significance of dishevelled in human glioma
Li, J., Guo, G., Li, J., Hao, J.-H., Zhang, J., Guo, Y., & Yu, H. (2014) · Journal of Surgical Research · doi:10.1016/j.jss.2014.06.034 · Cited by 19 · see citing works
“[26] Tolwinski NS, Wieschaus E.”
The Genomics of Colorectal Cancer: State of the Art
Beggs, A. D., & Hodgson, S. V. (2008) · Current Genomics · doi:10.2174/138920208783884865 · Cited by 18 · see citing works
“The Wnt glycoprotein binds to the transmembrane receptor frizzled and low-density lipoprotein receptor-related protein LRP-5/6 which leads to phosphorlation of LRP by GSK-3 and CK1 thus causing recruitment of axin to the cell membrane [59].”
BackgroundXenopus paraxial protocadherin inhibits Wnt/β‐catenin signalling via casein kinase 2β
Kietzmann, A., Wang, Y., Weber, D., & Steinbeißer, H. (2011) · EMBO Reports · doi:10.1038/embor.2011.240 · Cited by 17 · see citing works
“Misregulation of this pathway can perturb embryogenesis, can lead to defects in organ formation and growth, and has been found in multiple human cancers (Tolwinski & Wieschaus, 2004).”
- Authors
- Tolwinski, N. S., & Wieschaus, E.
- Affiliations
- Howard Hughes Medical Institute (US)
- Corresponding author
- Wieschaus, Eric
- Venue
- Trends in Genetics
- Publisher
- Elsevier BV
- Published
- 2004-04
- Volume
- 20
- Issue
- 4
- Pages
- 177-181
- ISSN
- 0168-9525 (ISSN-L)
- OpenAlex
- W1965204519
- Cited by
- 151
- References
- 40
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 1 · 2022: 2 · 2021: 1 · 2020: 2 · 2017: 5 · 2016: 3 · 2015: 3 · 2014: 5 · 2013: 9 · 2012: 7
- FWCI
- 1.42
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Trends in Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Javna Agencija za Raziskovalno Dejavnost RS
- National Cancer Institute (P01CA041086, P01CA41086)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- Wnt signaling, armadillos, arrows, signal transduction, transcriptional activation
- MeSH terms
- Animals, Cell Membrane, Cell Nucleus, Models, Biological, Phosphorylation, Protein Binding, Proto-Oncogene Proteins, Signal Transduction, Zebrafish Proteins, Wnt Proteins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
