The APC tumour suppressor has a nuclear export function
Abstract
The adenomatous polpyposis coli (APC) protein is mutated in most colorectal tumours. Nearly all APC mutations are truncations, and many of these terminate in the mutation cluster region located halfway through the protein. In cancer cells expressing mutant APC, beta-catenin is stabilized and translocates into the nucleus to act as a transcriptional co-activator of T-cell factor. During normal development, APC also promotes the destabilization of beta-catenin and Drosophila Armadillo. It does so by binding to the Axin complex which earmarks beta-catenin/Armadillo for degradation by the proteasome pathway. APC has a regulatory role in this process, which is poorly understood. Here we show that APC contains highly conserved nuclear export signals 3' adjacent to the mutation cluster region that enable it to exit from the nucleus. This ability is lost in APC mutant cancer cells, and we provide evidence that beta-catenin accumulates in the nucleus as a result. Thus, the ability of APC to exit from the nucleus appears to be critical for its tumour suppressor function.
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Asymmetric membrane accumulation of Dsh is important for the non-canonical pathway and convergent extension movements.
“As mentioned above, asymmetric membrane accumulation of Dsh is important for the non-canonical pathway and convergent extension movements.118–120”
From Wnt signal transduction pathways (2008) · cites this paper as [119]
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“…between the nucleus and cytoplasmic compartment, thereby escorting β-catenin to the cytosol, where it is targeted by phosphorylation for ubiquitination and ultimately proteosomal degradation (Henderson, 2000; Henderson & Fagotto, 2002; RosinArbesfeld et al., 2003; Rosin-Arbesfeld et al., 2000).”
BackgroundAPC Is Essential for Targeting Phosphorylated β-Catenin to the SCFβ-TrCP Ubiquitin Ligase
Su, Y., Fu, C., Ishikawa, S., Stella, A., Kojima, M., Shitoh, K., Schreiber, E. M., Day, B. W., & Liu, B. (2008) · Molecular Cell · doi:10.1016/j.molcel.2008.10.023 · Cited by 174 · see citing works
“Second, it may sequester b-catenin in the cytoplasm, thereby preventing its association with Tcf4 in the nucleus (Neufeld et al., 2000; Rosin-Arbesfeld et al., 2000).”
APC‐mediated downregulation of β‐catenin activity involves nuclear sequestration and nuclear export
Neufeld, K. L., Zhang, F., Cullen, B. R., & White, R. L. (2000) · EMBO Reports · doi:10.1093/embo-reports/kvd117 · Cited by 174 · see citing works
“Although the three putative NESs identified in the central third of APC protein may function in Drosophila APC (Rosin-Arbfeld et al., 2000), with full-length human APC, mutation of the N-terminal two NESs results in a predominant nuclear localization, suggesting minimal activity of other NESs…”
BackgroundInfluentialProlyl isomerase Pin1: a catalyst for oncogenesis and a potential therapeutic target in cancer
Ryo, A., Liou, Y., Lu, K. P., & Wulf, G. M. (2003) · Journal of Cell Science · doi:10.1242/jcs.00276 · Cited by 172 · see citing works
“APC is the shuttling protein that exports nuclear β-catenin to the cytoplasm for degradation (Bienz, 2002; Henderson, 2000; Neufeld et al., 2000; Rosin-Arbesfeld et al., 2000).”
BackgroundWnt signalling and the mechanistic basis of tumour development
Ilyas, M. (2005) · The Journal of Pathology · doi:10.1002/path.1692 · Cited by 171 · see citing works
β-catenin is a downstream effector of Wnt-mediated tumorigenesis in the mammary gland
Michaelson, J. S., & Leder, P. (2001) · Oncogene · doi:10.1038/sj.onc.1204586 · Cited by 163 · see citing works
Protocadherins at the Crossroad of Signaling Pathways
Pancho, A., Aerts, T., Mitsogiannis, M. D., & Seuntjens, E. (2020) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2020.00117 · Cited by 189 · see citing works
Xing, Y., Clements, W. K., Trong, I. L., Hinds, T. R., Stenkamp, R. E., Kimelman, D., & Xu, W. (2004) · Molecular Cell · doi:10.1016/j.molcel.2004.08.001 · Cited by 156 · see citing works
Immune Inspired Somatic Contiguous Hypermutation for Function Optimisation
Kelsey, J., & Timmis, J. (2003) · Lecture notes in computer science · doi:10.1007/3-540-45105-6_26 · Cited by 155 · see citing works
Protein and RNA Export from the Nucleus
Lei, E. P., & Silver, P. A. (2002) · Developmental Cell · doi:10.1016/s1534-5807(02)00134-x · Cited by 155 · see citing works
The APC Tumor Suppressor Binds to C-Terminal Binding Protein to Divert Nuclear β-Catenin from TCF
Hamada, F., & Bienz, M. (2004) · Developmental Cell · doi:10.1016/j.devcel.2004.08.022 · Cited by 154 · see citing works
“EGF receptor/Rolled MAP kinase assay system (Promega) as described (Rosin-Arbesfeld et al., 2000). signalling protects cells against activated Armadillo in the DrosophTo stimulate pTOPFLASH, pEGFP-C1-S33A human -catenin (pro- ila eye.”
BackgroundMethodSelf-citationNotch and Wnt inhibitors as potential new drugs for intestinal neoplastic disease
van Es, J. H., & Clevers, H. C. (2005) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2005.09.008 · Cited by 152 · see citing works
Ligand-dependent inhibition of β-catenin/TCF signaling by androgen receptor
Chesire, D. R., & Isaacs, W. B. (2002) · Oncogene · doi:10.1038/sj.onc.1206049 · Cited by 151 · see citing works
“Indeed, the determinants that govern nuclear localization of activated b-catenin are not completely understood; however, work has implicated TCFs and APC in this process (Huber et al., 1996; Henderson, 2000; Rosin-Arbesfeld et al., 2000).”
BackgroundGasca, S., Cañizares, J., Barbara, P. D. S., Méjean, C., Poulat, F., Berta, P., & Boizet-Bonhoure, B. (2002) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.172383099 · Cited by 154 · see citing works
Regulation of β-Catenin Function by the IκB Kinases
Lamberti, C., Lin, K., Yamamoto, Y., Verma, U. N., Verma, I. M., Byers, S., & Gaynor, R. B. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m104227200 · Cited by 147 · 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
Self-citationSimilarities between the Hedgehog and Wnt signaling pathways
Kalderon, D. (2002) · Trends in Cell Biology · doi:10.1016/s0962-8924(02)02388-7 · Cited by 141 · see citing works
Chibby cooperates with 14-3-3 to regulate β-catenin subcellular distribution and signaling activity
Li, F., Mofunanya, A., Harris, K., & Takemaru, K. (2008) · The Journal of Cell Biology · doi:10.1083/jcb.200709091 · Cited by 140 · see citing works
“The online version of this paper contains supplemental material.”
BackgroundThe Ubiquitin-Specific Protease USP34 Regulates Axin Stability and Wnt/β-Catenin Signaling
Lui, T. T. H., Lacroix, C., Ahmed, S. M., Goldenberg, S. J., Leach, C. A., Daulat, A. M., & Angers, S. (2011) · Molecular and Cellular Biology · doi:10.1128/mcb.01094-10 · Cited by 138 · see citing works
“Indeed, APC contains bipartite nuclear localization and nuclear export signals that promote its nuclear cytoplasmic shuttling (18, 40, 46).”
BackgroundWnt-signalling pathway in ovarian epithelial tumours: increased expression of β-catenin and GSK3β
Rask, K., Nilsson, A., Brännström, M., Carlsson, P., Hellberg, P., Janson, P. O., Hedin, L., & Sundfeldt, K. (2003) · British Journal of Cancer · doi:10.1038/sj.bjc.6601265 · Cited by 138 · see citing works
“This is followed by transcriptional activation of target genes, that is, c-myc, E-cadherin and cyclin D1 (reviewed by Roose and Clevers, 1999).”
BackgroundRosin‐Arbesfeld, R., Ihrke, G., & Bienz, M. (2001) · The EMBO Journal · doi:10.1093/emboj/20.21.5929 · Cited by 135 · see citing works
Self-citationFaux, M. C., Ross, J., Meeker, C. T., Johns, T. G., Ji, H. L., Simpson, R. J., Layton, M. J., & Burgess, A. W. (2003) · Journal of Cell Science · doi:10.1242/jcs.00862 · Cited by 135 · see citing works
“Mice with SW480APC xenografts were observed for 60 days.”
BackgroundMethodMolecular causes of colon cancer
Oving, I. M., & Clevers, H. C. (2002) · European Journal of Clinical Investigation · doi:10.1046/j.1365-2362.2002.01004.x · Cited by 135 · see citing works
The Wnt /β-catenin signaling pathway in the adult neurogenesis
Zhang, L., Yang, X., Yang, S., & Zhang, J. (2010) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2010.7483.x · Cited by 134 · see citing works
“This positively charged groove may serve as a binding surface for several proteins, including TCF (Behrens et al., 1996; Huber et al., 1996; Molenaar et al., 1996; Brunner et al., 1997; van de Wetering et al., 1997), adenomatous polyposis coli (APC; Rubinfeld et al., 1993) and adherens junction protein E-cadherin (Hul…”
BackgroundInfluentialSpink, K. E., Fridman, S. G., & Weis, W. I. (2001) · The EMBO Journal · doi:10.1093/emboj/20.22.6203 · Cited by 133 · see citing works
Targeted inactivation of CTNNB1 reveals unexpected effects of β-catenin mutation
Chan, T. A.-T., Wang, Z., Dang, L. H., Vogelstein, B., & Kinzler, K. W. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.082240999 · Cited by 130 · see citing works
The rules and roles of nucleocytoplasmic shuttling proteins
Gama‐Carvalho, M., & Carmo‐Fonseca, M. (2001) · FEBS Letters · doi:10.1016/s0014-5793(01)02487-5 · Cited by 129 · see citing works
Rada, C. A., Jarvis, J. M., & Milstein, C. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.092160999 · Cited by 128 · see citing works
Dancing in and out of the nucleus: p120ctn and the transcription factor Kaiso
Daniel, J. M. (2006) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2006.08.052 · Cited by 126 · see citing works
The adenomatous polyposis coli (APC) tumour suppressor – genetics, function and disease
Sieber, O. M., Tomlinson, I. P. M., & Lamlum, H. (2000) · Molecular Medicine Today · doi:10.1016/s1357-4310(00)01828-1 · Cited by 123 · see citing works
Tran, H., Hamada, F., Schwarz, T., & Bienz, M. (2008) · Genes & Development · doi:10.1101/gad.463208 · Cited by 122 · see citing works
“APC and E-APC plasmids were generated previously (Hamada and Bienz 2002; Rosin-Arbesfeld et al. 2003), except for APC(1–1447) (kindly provided by J. Worm).”
BackgroundSelf-citationIdentification of a Nuclear Export Signal in the Catalytic Subunit of AMP-activated Protein Kinase
Kazgan, N., Williams, T., Forsberg, L. J., & Brenman, J. E. (2010) · Molecular Biology of the Cell · doi:10.1091/mbc.e10-04-0347 · Cited by 117 · see citing works
“…both GFP- and mCherry-tagged AMPK increased nuclear enrichment upon heat shock (Figure 6, D and E), other GFP-tagged proteins, including APC2, which contains both NES (Rosin-Arbesfeld et al., 2000) and NLS (Zhang et al., 2000) sequences, did not localize to the nucleus under heat shock (Figure 6F).”
BackgroundTwo βs or not two βs: regulation of asymmetric division by β-catenin
Mizumoto, K., & Sawa, H. (2007) · Trends in Cell Biology · doi:10.1016/j.tcb.2007.08.004 · Cited by 120 · see citing works
Suppressor of Fused Negatively Regulates β-Catenin Signaling
Meng, X., Poon, R. W. M., Zhang, X., Cheah, A. Y. L., Ding, Q., Hui, C., & Alman, B. A. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m105317200 · Cited by 119 · see citing works
Dehner, M., Hadjihannas, M. V., Weiske, J., Huber, O., & Behrens, J. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m710366200 · Cited by 116 · see citing works
Haegele, L., Ingold, B., Naumann, H., Tabatabai, G., Ledermann, B., & Brandner, S. (2003) · Molecular and Cellular Neuroscience · doi:10.1016/s1044-7431(03)00232-x · Cited by 117 · see citing works
Nuclear-Cytoplasmic Shuttling of Menin Regulates Nuclear Translocation of β-Catenin
Cao, Y., Liu, R., Jiang, X., Lu, J., Jiang, J., Zhang, C. X., Li, X., & Ning, G. (2009) · Molecular and Cellular Biology · doi:10.1128/mcb.00335-09 · Cited by 116 · see citing works
“The subcellular localization and activity of -catenin are directly controlled by numerous molecules through regulating its stability and transport (8, 14, 35).”
BackgroundZhang, F., White, R. L., & Neufeld, K. L. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.230435597 · Cited by 116 · see citing works
Beta-catenin signaling in prostate cancer: an early perspective.
Chesire, D. R., & Isaacs, W. B. (2003) · Endocrine Related Cancer · doi:10.1677/erc.0.0100537 · Cited by 115 · see citing works
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Identification of the Axin and Frat Binding Region of Glycogen Synthase Kinase-3
Fraser, E., Young, N., Dajani, R. B., Franca‐Koh, J., Ryves, J., Williams, R. S. B., Yeo, M., Webster, M.-T., Richardson, C. D., Smalley, M. J., et al. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m109462200 · Cited by 114 · see citing works
Targeting nucleocytoplasmic transport in cancer therapy
Hill, R., Cautain, B., de Pedro, N., & Link, W. (2013) · Oncotarget · doi:10.18632/oncotarget.1457 · Cited by 112 · see citing works
“β-catenin can also be transported back into the cytoplasm bound to Axin (a negative regulator of the Wnt signalling pathway), independent of its degradation role [70] or when in a protein complex with APC, migrating from the cytoplasm and the nucleus [71].”
BackgroundWnt Signaling: Physiology and Pathology
Prunier, C., Hocevar, B. A., & Howe, P. H. (2004) · Growth Factors · doi:10.1080/08977190410001720860 · Cited by 108 · see citing works
“APC, through its nuclear export signals (NES) and its ability to shuttle between the cytoplasm and nucleus, has also been proposed to regulate b-catenin levels by capturing and escorting nuclear b-catenin to the cytoplasm for degradation (Henderson, 2000; Neufeld et al., 2000; Rosin-Arbesfeld et al., 2000; 2003; Hende…”
BackgroundArmadillo 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
Phillips, R. S., Ramos, S. B. V., & Blackshear, P. J. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m111457200 · Cited by 108 · see citing works
- Authors
- Rosin-Arbesfeld, R., Townsley, F., & Bienz, M.
- Affiliations
- MRC Laboratory of Molecular Biology (GB)
- Corresponding author
- Bienz, Mariann
- ORCID
- Bienz, Mariann
- Venue
- Nature
- Published
- 2000-08
- Volume
- 406
- Issue
- 6799
- Pages
- 1009-1012
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1666932156
- Cited by
- 343
- References
- 30
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 3 · 2023: 1 · 2022: 7 · 2021: 4 · 2020: 6 · 2019: 4 · 2018: 8 · 2017: 4 · 2016: 6 · 2015: 6 · 2014: 7 · 2013: 12 · 2012: 10
- FWCI
- 15.18
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Keywords
- nuclear export, nuclear export signal, β-catenin stabilization, colorectal cancer, proteasomal degradation, armadillos, mutation cluster region, tumor suppressor function
- MeSH terms
- Amino Acid Sequence, Animals, Biological Transport, Cell Nucleus, Cytoskeletal Proteins, Drosophila, Fatty Acids, Unsaturated, Multigene Family, Genetic Complementation Test, Humans, Molecular Sequence Data, Mutation, Peptide Fragments, Recombinant Fusion Proteins, Transfection, Tumor Cells, Cultured, Colorectal Neoplasms, Trans-Activators, Conserved Sequence, Genes, Reporter, COS Cells, Adenomatous Polyposis Coli Protein, beta Catenin
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