J. Cell Biol., Volume 145, Number 4, May 17, 1999 741-756

Domains of Axin Involved in Protein-Protein Interactions, Wnt Pathway Inhibition, and Intracellular Localization

François Fagotto,^* Eek-hoon Jho, Li Zeng, Thomas Kurth,^* Thomas Joos,^* Christine Kaufmann,^* and Frank Costantini

^* Division of Cell Biology, Max-Planck Institute for Developmental Biology, 72076 Tübingen, Germany; and  Department of Genetics and Development, College of Physicians and Surgeons, Columbia University, New York 10032

Axin was identified as a regulator of embryonic axis induction in vertebrates that inhibits the Wnt signal transduction pathway. Epistasis experiments in frog embryos indicated that Axin functioned downstream of glycogen synthase kinase 3 (GSK3) and upstream of -catenin, and subsequent studies showed that Axin is part of a complex including these two proteins and adenomatous polyposis coli (APC). Here, we examine the role of different Axin domains in the effects on axis formation and -catenin levels. We find that the regulators of G-protein signaling domain (major APC-binding site) and GSK3-binding site are required, whereas the COOH-terminal sequences, including a protein phosphatase 2A binding site and the DIX domain, are not essential. Some forms of Axin lacking the -catenin binding site can still interact indirectly with -catenin and regulate -catenin levels and axis formation. Thus in normal embryonic cells, interaction with APC and GSK3 is critical for the ability of Axin to regulate signaling via -catenin. Myc-tagged Axin is localized in a characteristic pattern of intracellular spots as well as at the plasma membrane. NH₂-terminal sequences were required for targeting to either of these sites, whereas COOH-terminal sequences increased localization at the spots. Coexpression of hemagglutinin-tagged Dishevelled (Dsh) revealed strong colocalization with Axin, suggesting that Dsh can interact with the Axin/APC/GSK3/-catenin complex, and may thus modulate its activity.

-catenin;  glycogen synthase kinase 3 (GSK3);  adenomatous polyposis coli (APC);  Dishevelled (Dsh);  dorsal axis formation

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Chia, I. V., Kim, M. J., Itoh, K., Sokol, S. Y., Costantini, F. (2009). Both the RGS Domain and the Six C-Terminal Amino Acids of Mouse Axin Are Required for Normal Embryogenesis. Genetics 181: 1359-1368 [Abstract] [Full Text]  
• Salisbury, T. B., Binder, A. K., Grammer, J. C., Nilson, J. H. (2009). GnRH-Regulated Expression of Jun and JUN Target Genes in Gonadotropes Requires a Functional Interaction between TCF/LEF Family Members and {beta}-Catenin. Mol. Endocrinol. 23: 402-411 [Abstract] [Full Text]  
• Singh, A. K., Gupta, S., Jiang, Y., Younus, M., Ramzan, M. (2009). In vitro Neurogenesis from Neural Progenitor Cells Isolated from the Hippocampus Region of the Brain of Adult Rats Exposed to Ethanol during Early Development through Their Alcohol-Drinking Mothers. Alcohol Alcohol 44: 185-198 [Abstract] [Full Text]  
• Kim, M. J., Chia, I. V., Costantini, F. (2008). SUMOylation target sites at the C terminus protect Axin from ubiquitination and confer protein stability. FASEB J. 22: 3785-3794 [Abstract] [Full Text]  
• Cselenyi, C. S., Jernigan, K. K., Tahinci, E., Thorne, C. A., Lee, L. A., Lee, E. (2008). LRP6 transduces a canonical Wnt signal independently of Axin degradation by inhibiting GSK3's phosphorylation of {beta}-catenin. Proc. Natl. Acad. Sci. USA 105: 8032-8037 [Abstract] [Full Text]  
• Lu, Z., Liu, W., Huang, H., He, Y., Han, Y., Rui, Y., Wang, Y., Li, Q., Ruan, K., Ye, Z., Low, B. C., Meng, A., Lin, S.-C. (2008). Protein Encoded by the AxinFu Allele Effectively Down-regulates Wnt Signaling but Exerts a Dominant Negative Effect on c-Jun N-terminal Kinase Signaling. J. Biol. Chem. 283: 13132-13139 [Abstract] [Full Text]  
• Hayward, P., Kalmar, T., Martinez Arias, A. (2008). Wnt/Notch signalling and information processing during development. Development 135: 411-424 [Abstract] [Full Text]  
• Zeng, X., Huang, H., Tamai, K., Zhang, X., Harada, Y., Yokota, C., Almeida, K., Wang, J., Doble, B., Woodgett, J., Wynshaw-Boris, A., Hsieh, J.-C., He, X. (2008). Initiation of Wnt signaling: control of Wnt coreceptor Lrp6 phosphorylation/activation via frizzled, dishevelled and axin functions. Development 135: 367-375 [Abstract] [Full Text]  
• Saaf, A. M., Halbleib, J. M., Chen, X., Yuen, S. T., Leung, S. Y., Nelson, W. J., Brown, P. O. (2007). Parallels between Global Transcriptional Programs of Polarizing Caco-2 Intestinal Epithelial Cells In Vitro and Gene Expression Programs in Normal Colon and Colon Cancer. Mol. Biol. Cell 18: 4245-4260 [Abstract] [Full Text]  
• Eisinger, A. L., Nadauld, L. D., Shelton, D. N., Prescott, S. M., Stafforini, D. M., Jones, D. A. (2007). Retinoic Acid Inhibits beta-Catenin through Suppression of Cox-2: A ROLE FOR TRUNCATED ADENOMATOUS POLYPOSIS COLI. J. Biol. Chem. 282: 29394-29400 [Abstract] [Full Text]  
• Schwarz-Romond, T., Metcalfe, C., Bienz, M. (2007). Dynamic recruitment of axin by Dishevelled protein assemblies. J. Cell Sci. 120: 2402-2412 [Abstract] [Full Text]  
• Salisbury, T. B., Binder, A. K., Grammer, J. C., Nilson, J. H. (2007). Maximal Activity of the Luteinizing Hormone{beta}-Subunit Gene Requires {beta}-Catenin. Mol. Endocrinol. 21: 963-971 [Abstract] [Full Text]  
• Parakh, T. N., Hernandez, J. A., Grammer, J. C., Weck, J., Hunzicker-Dunn, M., Zeleznik, A. J., Nilson, J. H. (2006). Follicle-stimulating hormone/cAMP regulation of aromatase gene expression requires beta-catenin. Proc. Natl. Acad. Sci. USA 103: 12435-12440 [Abstract] [Full Text]  
• Chen, H.-J., Lin, C.-M., Lin, C.-S., Perez-Olle, R., Leung, C. L., Liem, R. K.H. (2006). The role of microtubule actin cross-linking factor 1 (MACF1) in the Wnt signaling pathway. Genes Dev. 20: 1933-1945 [Abstract] [Full Text]  
• Seto, E. S., Bellen, H. J. (2006). Internalization is required for proper Wingless signaling in Drosophila melanogaster.. JCB 173: 95-106 [Abstract] [Full Text]  
• Tan, J., Geng, L., Yazlovitskaya, E. M., Hallahan, D. E. (2006). Protein Kinase B/Akt-Dependent Phosphorylation of Glycogen Synthase Kinase-3{beta} in Irradiated Vascular Endothelium. Cancer Res. 66: 2320-2327 [Abstract] [Full Text]  
• Smalley, M. J., Signoret, N., Robertson, D., Tilley, A., Hann, A., Ewan, K., Ding, Y., Paterson, H., Dale, T. C. (2005). Dishevelled (Dvl-2) activates canonical Wnt signalling in the absence of cytoplasmic puncta. J. Cell Sci. 118: 5279-5289 [Abstract] [Full Text]  
• Schwarz-Romond, T., Merrifield, C., Nichols, B. J., Bienz, M. (2005). The Wnt signalling effector Dishevelled forms dynamic protein assemblies rather than stable associations with cytoplasmic vesicles. J. Cell Sci. 118: 5269-5277 [Abstract] [Full Text]  
• Wallingford, J. B., Habas, R. (2005). The developmental biology of Dishevelled: an enigmatic protein governing cell fate and cell polarity. Development 132: 4421-4436 [Abstract] [Full Text]  
• Reintsch, W. E., Habring-Mueller, A., Wang, R. W., Schohl, A., Fagotto, F. (2005). {beta}-Catenin controls cell sorting at the notochord-somite boundary independently of cadherin-mediated adhesion. JCB 170: 675-686 [Abstract] [Full Text]  
• Chia, I. V., Costantini, F. (2005). Mouse Axin and Axin2/Conductin Proteins Are Functionally Equivalent In Vivo. Mol. Cell. Biol. 25: 4371-4376 [Abstract] [Full Text]  
• Yu, H.-M. I., Jerchow, B., Sheu, T.-J., Liu, B., Costantini, F., Puzas, J. E., Birchmeier, W., Hsu, W. (2005). The role of Axin2 in calvarial morphogenesis and craniosynostosis. Development 132: 1995-2005 [Abstract] [Full Text]  
• Salahshor, S, Woodgett, J R (2005). The links between axin and carcinogenesis. J. Clin. Pathol. 58: 225-236 [Abstract] [Full Text]  
• Choi, J., Park, S. Y., Costantini, F., Jho, E.-h., Joo, C.-K. (2004). Adenomatous Polyposis Coli Is Down-regulated by the Ubiquitin-Proteasome Pathway in a Process Facilitated by Axin. J. Biol. Chem. 279: 49188-49198 [Abstract] [Full Text]  
• Papadopoulou, D., Bianchi, M. W., Bourouis, M. (2004). Functional Studies of Shaggy/Glycogen Synthase Kinase 3 Phosphorylation Sites in Drosophila melanogaster. Mol. Cell. Biol. 24: 4909-4919 [Abstract] [Full Text]  
• He, X., Semenov, M., Tamai, K., Zeng, X. (2004). LDL receptor-related proteins 5 and 6 in Wnt/{beta}-catenin signaling: Arrows point the way. Development 131: 1663-1677 [Abstract] [Full Text]  
• Wiechens, N., Heinle, K., Englmeier, L., Schohl, A., Fagotto, F. (2004). Nucleo-cytoplasmic Shuttling of Axin, a Negative Regulator of the Wnt-{beta}-Catenin Pathway. J. Biol. Chem. 279: 5263-5267 [Abstract] [Full Text]  
• Yang, J., Wu, J., Tan, C., Klein, P. S. (2003). PP2A:B56{epsilon} is required for Wnt/{beta}-catenin signaling during embryonic development. Development 130: 5569-5578 [Abstract] [Full Text]  
• Kim, S., Lee, J., Park, J., Chung, J. (2003). BP75, Bromodomain-containing Mr 75,000 Protein, Binds Dishevelled-1 and Enhances Wnt Signaling by Inactivating Glycogen Synthase Kinase-3{beta}. Cancer Res. 63: 4792-4795 [Abstract] [Full Text]  
• Valenta, T., Lukas, J., Korinek, V. (2003). 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 31: 2369-2380 [Abstract] [Full Text]  
• Kim, J. W., Lee, J. E., Kim, M. J., Cho, E.-G., Cho, S.-G., Choi, E.-J. (2003). Glycogen Synthase Kinase 3beta Is a Natural Activator of Mitogen-activated Protein Kinase/Extracellular Signal-regulated Kinase Kinase Kinase 1 (MEKK1). J. Biol. Chem. 278: 13995-14001 [Abstract] [Full Text]  
• Hino, S.-i., Michiue, T., Asashima, M., Kikuchi, A. (2003). Casein Kinase Iepsilon Enhances the Binding of Dvl-1 to Frat-1 and Is Essential for Wnt-3a-induced Accumulation of beta -Catenin. J. Biol. Chem. 278: 14066-14073 [Abstract] [Full Text]  
• Lyu, J., Costantini, F., Jho, E.-h., Joo, C.-k. (2003). Ectopic Expression of Axin Blocks Neuronal Differentiation of Embryonic Carcinoma P19 Cells. J. Biol. Chem. 278: 13487-13495 [Abstract] [Full Text]  
• Bilello, J. P., Cable, E. E., Isom, H. C. (2003). Expression of E-Cadherin and Other Paracellular Junction Genes Is Decreased in Iron-Loaded Hepatocytes. Am. J. Pathol. 162: 1323-1338 [Abstract] [Full Text]  
• Bek, S., Kemler, R. (2003). Protein kinase CKII regulates the interaction of {beta}-catenin with {alpha}-catenin and its protein stability. J. Cell Sci. 115: 4743-4753 [Abstract] [Full Text]  
• Karasawa, T., Yokokura, H., Kitajewski, J., Lombroso, P. J. (2002). Frizzled-9 Is Activated by Wnt-2 and Functions in Wnt/beta -Catenin Signaling. J. Biol. Chem. 277: 37479-37486 [Abstract] [Full Text]  
• Zhang, Y., Qiu, W.-J., Chan, S. C., Han, J., He, X., Lin, S.-C. (2002). Casein Kinase I and Casein Kinase II Differentially Regulate Axin Function in Wnt and JNK Pathways. J. Biol. Chem. 277: 17706-17712 [Abstract] [Full Text]  
• Ferkey, D. M., Kimelman, D. (2002). Glycogen Synthase Kinase-3beta Mutagenesis Identifies a Common Binding Domain for GBP and Axin. J. Biol. Chem. 277: 16147-16152 [Abstract] [Full Text]  
• Jho, E.-h., Zhang, T., Domon, C., Joo, C.-K., Freund, J.-N., Costantini, F. (2002). Wnt/{beta}-Catenin/Tcf Signaling Induces the Transcription of Axin2, a Negative Regulator of the Signaling Pathway. Mol. Cell. Biol. 22: 1172-1183 [Abstract] [Full Text]  
• Hsu, W., Shakya, R., Costantini, F. (2001). Impaired mammary gland and lymphoid development caused by inducible expression of Axin in transgenic mice. JCB 155: 1055-1064 [Abstract] [Full Text]  
• Rubinfeld, B., Tice, D. A., Polakis, P. (2001). Axin-dependent Phosphorylation of the Adenomatous Polyposis Coli Protein Mediated by Casein Kinase 1epsilon. J. Biol. Chem. 276: 39037-39045 [Abstract] [Full Text]  
• Dahmen, R. P., Koch, A., Denkhaus, D., Tonn, J. C., Sorensen, N., Berthold, F., Behrens, J., Birchmeier, W., Wiestler, O. D., Pietsch, T. (2001). Deletions of AXIN1, a Component of the WNT/wingless Pathway, in Sporadic Medulloblastomas. Cancer Res. 61: 7039-7043 [Abstract] [Full Text]  
• Furuhashi, M., Yagi, K., Yamamoto, H., Furukawa, Y., Shimada, S., Nakamura, Y., Kikuchi, A., Miyazono, K., Kato, M. (2001). Axin Facilitates Smad3 Activation in the Transforming Growth Factor {beta} Signaling Pathway. Mol. Cell. Biol. 21: 5132-5141 [Abstract] [Full Text]  
• Tolwinski, N. S., Wieschaus, E. (2001). Armadillo nuclear import is regulated by cytoplasmic anchor Axin and nuclear anchor dTCF/Pan. Development 128: 2107-2117 [Abstract] [Full Text]  
• Fearnhead, N. S., Britton, M. P., Bodmer, W. F. (2001). The ABC of APC. Hum Mol Genet 10: 721-733 [Abstract] [Full Text]  
• Reinacher-Schick, A., Gumbiner, B. M. (2001). Apical Membrane Localization of the Adenomatous Polyposis Coli Tumor Suppressor Protein and Subcellular Distribution of the {beta}-Catenin Destruction Complex in Polarized Epithelial Cells. JCB 152: 491-502 [Abstract] [Full Text]  
• Hino, S.-i., Kishida, S., Michiue, T., Fukui, A., Sakamoto, I., Takada, S., Asashima, M., Kikuchi, A. (2001). Inhibition of the Wnt Signaling Pathway by Idax, a Novel Dvl-Binding Protein. Mol. Cell. Biol. 21: 330-342 [Abstract] [Full Text]  
• Krylova, O., Messenger, M. J., Salinas, P. C. (2000). Dishevelled-1 Regulates Microtubule Stability: A New Function Mediated by Glycogen Synthase Kinase-3{beta}. JCB 151: 83-94 [Abstract] [Full Text]  
• Polakis, P. (2000). Wnt signaling and cancer. Genes Dev. 14: 1837-1851 [Full Text]  
• Torres, M. A., Nelson, W. J. (2000). Colocalization and Redistribution of Dishevelled and Actin during Wnt-induced Mesenchymal Morphogenesis. JCB 149: 1433-1442 [Abstract] [Full Text]  
• Zhurinsky, J., Shtutman, M., Ben-Ze'ev, A. (2000). Differential Mechanisms of LEF/TCF Family-Dependent Transcriptional Activation by beta -Catenin and Plakoglobin. Mol. Cell. Biol. 20: 4238-4252 [Abstract] [Full Text]  
• Pawson, T., Nash, P. (2000). Protein-protein interactions define specificity in signal transduction. Genes Dev. 14: 1027-1047 [Full Text]  
• Itoh, K., Antipova, A., Ratcliffe, M. J., Sokol, S. (2000). Interaction of Dishevelled and Xenopus Axin-Related Protein Is Required for Wnt Signal Transduction. Mol. Cell. Biol. 20: 2228-2238 [Abstract] [Full Text]  
• Zhang, Y., Neo, S. Y., Wang, X., Han, J., Lin, S.-C. (1999). Axin Forms a Complex with MEKK1 and Activates c-Jun NH2-terminal Kinase/Stress-activated Protein Kinase through Domains Distinct from Wnt Signaling. J. Biol. Chem. 274: 35247-35254 [Abstract] [Full Text]  
• McCartney, B. M., Dierick, H. A., Kirkpatrick, C., Moline, M. M., Baas, A., Peifer, M., Bejsovec, A. (1999). Drosophila APC2 Is a Cytoskeletally-associated Protein that Regulates Wingless Signaling in the Embryonic Epidermis. JCB 146: 1303-1318 [Abstract] [Full Text]  
• Willert, K, Logan, C., Arora, A, Fish, M, Nusse, R (1999). A Drosophila Axin homolog, Daxin, inhibits Wnt signaling. Development 126: 4165-4173 [Abstract]  
• Zhang, Y., Neo, S. Y., Han, J., Lin, S.-C. (2000). Dimerization Choices Control the Ability of Axin and Dishevelled to Activate c-Jun N-terminal Kinase/Stress-activated Protein Kinase. J. Biol. Chem. 275: 25008-25014 [Abstract] [Full Text]  
• Hinoi, T., Yamamoto, H., Kishida, M., Takada, S., Kishida, S., Kikuchi, A. (2000). Complex Formation of Adenomatous Polyposis Coli Gene Product and Axin Facilitates Glycogen Synthase Kinase-3beta -dependent Phosphorylation of beta -Catenin and Down-regulates beta -Catenin. J. Biol. Chem. 275: 34399-34406 [Abstract] [Full Text]  
• Sakamoto, I., Kishida, S., Fukui, A., Kishida, M., Yamamoto, H., Hino, S.-i., Michiue, T., Takada, S., Asashima, M., Kikuchi, A. (2000). A Novel beta -Catenin-binding Protein Inhibits beta -Catenin-dependent Tcf Activation and Axis Formation. J. Biol. Chem. 275: 32871-32878 [Abstract] [Full Text]  
• Kadoya, T., Kishida, S., Fukui, A., Hinoi, T., Michiue, T., Asashima, M., Kikuchi, A. (2000). Inhibition of Wnt Signaling Pathway by a Novel Axin-binding Protein. J. Biol. Chem. 275: 37030-37037 [Abstract] [Full Text]  
• Kishida, M., Hino, S.-i., Michiue, T., Yamamoto, H., Kishida, S., Fukui, A., Asashima, M., Kikuchi, A. (2001). Synergistic Activation of the Wnt Signaling Pathway by Dvl and Casein Kinase Iepsilon. J. Biol. Chem. 276: 33147-33155 [Abstract] [Full Text]  
• Zhang, Y., Qiu, W.-J., Liu, D.-X., Neo, S. Y., He, X., Lin, S.-C. (2001). Differential Molecular Assemblies Underlie the Dual Function of Axin in Modulating the Wnt and JNK Pathways. J. Biol. Chem. 276: 32152-32159 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents