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PMID: 10811618 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Structural basis of the Axin-adenomatous polyposis coli interaction.

The EMBO journal ·Vol. 19 ·No. 10 ·2000-05-15 ·Pages 2270-9

Spink KE, Polakis P, Weis WI

Abstract

Axin and the adenomatous polyposis coli (APC) tumor suppressor protein are components of the Wnt/Wingless growth factor signaling pathway. In the absence of Wnt signal, Axin and APC regulate cytoplasmic levels of the proto-oncogene beta-catenin through the formation of a large complex containing these three proteins, glycogen synthase kinase 3beta (GSK3beta) and several other proteins. Both Axin and APC are known to be critical for beta-catenin regulation, and truncations in APC that eliminate the Axin-binding site result in human cancers. A protease-resistant domain of Axin that contains the APC-binding site is a member of the regulators of G-protein signaling (RGS) superfamily. The crystal structures of this domain alone and in complex with an Axin-binding sequence from APC reveal that the Axin-APC interaction occurs at a conserved groove on a face of the protein that is distinct from the G-protein interface of classical RGS proteins. The molecular interactions observed in the Axin-APC complex provide a rationale for the evolutionary conservation seen in both proteins.

MeSH Terms
Adenomatous Polyposis Coli Protein Amino Acid Sequence Animals Axin Protein Binding Sites Cytoskeletal Proteins/chemistry,genetics,metabolism Humans Molecular Sequence Data Mutagenesis Protein Binding Protein Conformation Proteins/chemistry,genetics,metabolism Proto-Oncogene Mas Proto-Oncogene Proteins/metabolism Repressor Proteins Sequence Alignment Signal Transduction Wnt Proteins Xenopus Xenopus Proteins Zebrafish Proteins
Chemicals
Adenomatous Polyposis Coli Protein Axin Protein Cytoskeletal Proteins MAS1 protein, human Proteins Proto-Oncogene Mas Proto-Oncogene Proteins Repressor Proteins Wnt Proteins Xenopus Proteins Zebrafish Proteins axin1 protein, Xenopus
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Spink K E
Department of Structural Biology, Stanford University School of Medicine, 299 Campus Drive West, Stanford, CA 94305, USA.
Polakis P
Weis W I
References (52)
52 references, click to expand
  1. The oncogenic activation of beta-catenin.
    Curr Opin Genet Dev. 1999 Feb;9(1):15-21 PMID: 10072352
  2. Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells.
    Nature. 1999 Apr 1;398(6726):422-6 PMID: 10201372
  3. Functional domains of axin. Importance of the C terminus as an oligomerization domain.
    J Biol Chem. 1999 May 14;274(20):14090-3 PMID: 10318824
  4. The cyclin D1 gene is a target of the beta-catenin/LEF-1 pathway.
    Proc Natl Acad Sci U S A. 1999 May 11;96(10):5522-7 PMID: 10318916
  5. Interaction of axin and Dvl-2 proteins regulates Dvl-2-stimulated TCF-dependent transcription.
    EMBO J. 1999 May 17;18(10):2823-35 PMID: 10329628
  6. Domains of axin involved in protein-protein interactions, Wnt pathway inhibition, and intracellular localization.
    J Cell Biol. 1999 May 17;145(4):741-56 PMID: 10330403
  7. Solution structure of human GAIP (Galpha interacting protein): a regulator of G protein signaling.
    J Mol Biol. 1999 Aug 27;291(4):927-39 PMID: 10452897
  8. Drosophila APC2 is a cytoskeletally-associated protein that regulates wingless signaling in the embryonic epidermis.
    J Cell Biol. 1999 Sep 20;146(6):1303-18 PMID: 10491393
  9. Identification and characterization of E-APC, a novel Drosophila homologue of the tumour suppressor APC.
    Genes Cells. 1999 Aug;4(8):465-74 PMID: 10526234
  10. Divergence of RGS proteins: evidence for the existence of six mammalian RGS subfamilies.
    Trends Biochem Sci. 1999 Nov;24(11):411-4 PMID: 10542401
  11. A new Drosophila APC homologue associated with adhesive zones of epithelial cells.
    Nat Cell Biol. 1999 Jul;1(3):144-51 PMID: 10559900
  12. AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1.
    Nat Genet. 2000 Mar;24(3):245-50 PMID: 10700176
  13. WISP-1 is a Wnt-1- and beta-catenin-responsive oncogene.
    Genes Dev. 2000 Mar 1;14(5):585-95 PMID: 10716946
  14. Somatic mutations of the APC gene in colorectal tumors: mutation cluster region in the APC gene.
    Hum Mol Genet. 1992 Jul;1(4):229-33 PMID: 1338904
  15. Raster3D Version 2.0. A program for photorealistic molecular graphics.
    Acta Crystallogr D Biol Crystallogr. 1994 Nov 1;50(Pt 6):869-73 PMID: 15299354
  16. The CCP4 suite: programs for protein crystallography.
    Acta Crystallogr D Biol Crystallogr. 1994 Sep 1;50(Pt 5):760-3 PMID: 15299374
  17. Free R value: a novel statistical quantity for assessing the accuracy of crystal structures.
    Nature. 1992 Jan 30;355(6359):472-5 PMID: 18481394
  18. Eukaryotic proteins expressed in Escherichia coli: an improved thrombin cleavage and purification procedure of fusion proteins with glutathione S-transferase.
    Anal Biochem. 1991 Feb 1;192(2):262-7 PMID: 1852137
  19. Improved methods for building protein models in electron density maps and the location of errors in these models.
    Acta Crystallogr A. 1991 Mar 1;47 ( Pt 2):110-9 PMID: 2025413
  20. Processing of X-ray diffraction data collected in oscillation mode.
    Methods Enzymol. 1997;276:307-26 PMID: 27754618
  21. Regulation of intracellular beta-catenin levels by the adenomatous polyposis coli (APC) tumor-suppressor protein.
    Proc Natl Acad Sci U S A. 1995 Mar 28;92(7):3046-50 PMID: 7708772
  22. Association of the APC tumor suppressor protein with catenins.
    Science. 1993 Dec 10;262(5140):1734-7 PMID: 8259519
  23. Binding of GSK3beta to the APC-beta-catenin complex and regulation of complex assembly.
    Science. 1996 May 17;272(5264):1023-6 PMID: 8638126
  24. Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC.
    Science. 1997 Mar 21;275(5307):1787-90 PMID: 9065402
  25. Stabilization of beta-catenin by genetic defects in melanoma cell lines.
    Science. 1997 Mar 21;275(5307):1790-2 PMID: 9065403
  26. Structure of RGS4 bound to AlF4--activated G(i alpha1): stabilization of the transition state for GTP hydrolysis.
    Cell. 1997 Apr 18;89(2):251-61 PMID: 9108480
  27. LEF-1, a nuclear factor coordinating signaling inputs from wingless and decapentaplegic.
    Cell. 1997 Mar 21;88(6):777-87 PMID: 9118221
  28. Armadillo coactivates transcription driven by the product of the Drosophila segment polarity gene dTCF.
    Cell. 1997 Mar 21;88(6):789-99 PMID: 9118222
  29. The mouse Fused locus encodes Axin, an inhibitor of the Wnt signaling pathway that regulates embryonic axis formation.
    Cell. 1997 Jul 11;90(1):181-92 PMID: 9230313
  30. Autonomous and nonautonomous regulation of axis formation by antagonistic signaling via 7-span cAMP receptors and GSK3 in Dictyostelium.
    Genes Dev. 1997 Aug 15;11(16):2112-23 PMID: 9284050
  31. Beta-catenin mutations in cell lines established from human colorectal cancers.
    Proc Natl Acad Sci U S A. 1997 Sep 16;94(19):10330-4 PMID: 9294210
  32. A beta-catenin/XTcf-3 complex binds to the siamois promoter to regulate dorsal axis specification in Xenopus.
    Genes Dev. 1997 Sep 15;11(18):2359-70 PMID: 9308964
  33. Serine phosphorylation-regulated ubiquitination and degradation of beta-catenin.
    J Biol Chem. 1997 Oct 3;272(40):24735-8 PMID: 9312064
  34. Loss of beta-catenin regulation by the APC tumor suppressor protein correlates with loss of structure due to common somatic mutations of the gene.
    Cancer Res. 1997 Oct 15;57(20):4624-30 PMID: 9377578
  35. An extensively modified version of MolScript that includes greatly enhanced coloring capabilities.
    J Mol Graph Model. 1997 Apr;15(2):132-4, 112-3 PMID: 9385560
  36. Signal transduction by the Wnt family of ligands.
    Biochem J. 1998 Jan 15;329 ( Pt 2):209-23 PMID: 9425102
  37. 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 Mar 2;17(5):1371-84 PMID: 9482734
  38. Sporadic medulloblastomas contain oncogenic beta-catenin mutations.
    Cancer Res. 1998 Mar 1;58(5):896-9 PMID: 9500446
  39. Bridging of beta-catenin and glycogen synthase kinase-3beta by axin and inhibition of beta-catenin-mediated transcription.
    Proc Natl Acad Sci U S A. 1998 Mar 17;95(6):3020-3 PMID: 9501208
  40. Beta-catenin: a key mediator of Wnt signaling.
    Curr Opin Genet Dev. 1998 Feb;8(1):95-102 PMID: 9529612
  41. Mutations in the beta-catenin gene (CTNNB1) in endometrioid ovarian carcinomas.
    Cancer Res. 1998 Apr 1;58(7):1344-7 PMID: 9537226
  42. Functional interaction of an axin homolog, conductin, with beta-catenin, APC, and GSK3beta.
    Science. 1998 Apr 24;280(5363):596-9 PMID: 9554852
  43. 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 May 1;273(18):10823-6 PMID: 9556553
  44. Axil, a member of the Axin family, interacts with both glycogen synthase kinase 3beta and beta-catenin and inhibits axis formation of Xenopus embryos.
    Mol Cell Biol. 1998 May;18(5):2867-75 PMID: 9566905
  45. Wnt signaling and transcriptional control of Siamois in Xenopus embryos.
    Proc Natl Acad Sci U S A. 1998 May 12;95(10):5626-31 PMID: 9576934
  46. Downregulation of beta-catenin by human Axin and its association with the APC tumor suppressor, beta-catenin and GSK3 beta.
    Curr Biol. 1998 May 7;8(10):573-81 PMID: 9601641
  47. Activation of the beta-catenin gene in primary hepatocellular carcinomas by somatic alterations involving exon 3.
    Cancer Res. 1998 Jun 15;58(12):2524-7 PMID: 9635572
  48. Beta-catenin mutation in carcinoma of the uterine endometrium.
    Cancer Res. 1998 Aug 15;58(16):3526-8 PMID: 9721853
  49. Identification of c-MYC as a target of the APC pathway.
    Science. 1998 Sep 4;281(5382):1509-12 PMID: 9727977
  50. Crystallography & NMR system: A new software suite for macromolecular structure determination.
    Acta Crystallogr D Biol Crystallogr. 1998 Sep 1;54(Pt 5):905-21 PMID: 9757107
  51. Specific involvement of G proteins in regulation of serum response factor-mediated gene transcription by different receptors.
    J Biol Chem. 1998 Oct 16;273(42):27118-23 PMID: 9765229
  52. Identification of a domain of Axin that binds to the serine/threonine protein phosphatase 2A and a self-binding domain.
    J Biol Chem. 1999 Feb 5;274(6):3439-45 PMID: 9920888
Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1093/emboj/19.10.2270
Published
2000-05-15
Pages
2270-9
Language
English
Region
England
NLM ID
8208664
PMCID
PMC384355
Subset
IM
Grants
NIGMS NIH HHS · R01 GM056169 · United States
NIGMS NIH HHS · R01GM56169 · United States
External Links
PubMed source DOI: 10.1093/emboj/19.10.2270 PMC Full Text View journal details
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