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PMID:10318824

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Citation

Sakanaka, C and Williams, LT (1999) Functional domains of axin. Importance of the C terminus as an oligomerization domain. J. Biol. Chem. 274:14090-3

Abstract

To understand the mechanism of how Axin acts as an inhibitory molecule in the Wnt pathway, we generated a series of mutated forms of Axin. From the binding experiments, we defined the domains of Axin that bind glycogen synthase kinase-3beta (GSK-3beta) and beta-catenin. We also examined the ability of each Axin mutant to inhibit lymphoid enhancer factor-1 (Lef-1) reporter activity in a cell line expressing high levels of beta-catenin. Axin mutants that did not bind GSK-3beta or beta-catenin were ineffective in suppressing Lef-1 reporter activity. Binding GSK-3beta and beta-catenin was not sufficient for this inhibitory effect of Axin. Axin mutants with C-terminal truncations lacked the ability to inhibit Lef-1 reporter activity, even though they bound GSK-3beta and beta-catenin. The C-terminal region was required for binding to Axin itself. Substitution of the C-terminal region with an unrelated dimerizing molecule, the retinoid X receptor restored its inhibitory effect on Lef-1-dependent transcription. The oligomerization of Axin through its C terminus is important for its function in regulation of beta-catenin-mediated response.

Links

PubMed

Keywords

Animals; Axin Protein; Binding Sites; COS Cells; Calcium-Calmodulin-Dependent Protein Kinases/metabolism; Colonic Neoplasms/genetics; Colonic Neoplasms/metabolism; Cytoskeletal Proteins/metabolism; DNA-Binding Proteins/metabolism; Glycogen Synthase Kinase 3; Glycogen Synthase Kinases; Humans; Lymphoid Enhancer-Binding Factor 1; Mice; Mutagenesis, Site-Directed; Protein Conformation; Proteins/chemistry; Proteins/genetics; Proteins/physiology; Repressor Proteins; Structure-Activity Relationship; Trans-Activators; Transcription Factors/metabolism; Transcription, Genetic/drug effects; Tumor Cells, Cultured; beta Catenin

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:AXIN1

involved_in

GO:0034244: negative regulation of transcription elongation from RNA polymerase II promoter

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:AXIN1

enables

GO:0008013: beta-catenin binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q02248

F

Seeded From UniProt

complete

MOUSE:AXIN1

enables

GO:0042802: identical protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:O35625

F

Seeded From UniProt

complete

MOUSE:CTNB1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:O35625

F

Seeded From UniProt

complete

MOUSE:AXIN1

acts_upstream_of_or_within

GO:0034244: negative regulation of transcription elongation from RNA polymerase II promoter

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:AXIN1

acts_upstream_of_or_within

GO:0051260: protein homooligomerization

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:AXIN1

part_of

GO:0030877: beta-catenin destruction complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:AXIN1

enables

GO:0019901: protein kinase binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P49841

F

Seeded From UniProt

complete

MOUSE:AXIN1

enables

GO:0008022: protein C-terminus binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:AXIN1

enables

GO:0008013: beta-catenin binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q02248

F

Seeded From UniProt

complete

MOUSE:GSK3B

part_of

GO:0030877: beta-catenin destruction complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:CTNB1

part_of

GO:0030877: beta-catenin destruction complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete


See also

References

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