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PMID: 10330403 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Domains of axin involved in protein-protein interactions, Wnt pathway inhibition, and intracellular localization.

The Journal of cell biology ·Vol. 145 ·No. 4 ·1999-05-17 ·Pages 741-56

Fagotto F, Jho Eh, Zeng L, Kurth T, Joos T, Kaufmann C, Costantini F

Abstract

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 3beta (GSK3beta) and upstream of beta-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 beta-catenin levels. We find that the regulators of G-protein signaling domain (major APC-binding site) and GSK3beta-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 beta-catenin binding site can still interact indirectly with beta-catenin and regulate beta-catenin levels and axis formation. Thus in normal embryonic cells, interaction with APC and GSK3beta is critical for the ability of Axin to regulate signaling via beta-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/beta-catenin complex, and may thus modulate its activity.

MeSH Terms
Adaptor Proteins, Signal Transducing Adenomatous Polyposis Coli Protein Animals Axin Protein Calcium-Calmodulin-Dependent Protein Kinases/metabolism Cell Line Cytoskeletal Proteins/metabolism Dishevelled Proteins Glycogen Synthase Kinase 3 Glycogen Synthase Kinases Humans Intracellular Fluid/metabolism Mutagenesis Neoplasm Proteins/metabolism Phosphoproteins/metabolism Phosphorylation Proteins/chemistry,metabolism Proto-Oncogene Proteins/metabolism Repressor Proteins Structure-Activity Relationship Trans-Activators Wnt Proteins Xenopus/embryology Xenopus Proteins Zebrafish Proteins beta Catenin
Chemicals
Adaptor Proteins, Signal Transducing Adenomatous Polyposis Coli Protein Axin Protein CTNNB1 protein, Xenopus CTNNB1 protein, human Cytoskeletal Proteins DVL1 protein, Xenopus Dishevelled Proteins Neoplasm Proteins Phosphoproteins Proteins Proto-Oncogene Proteins Repressor Proteins Trans-Activators Wnt Proteins Xenopus Proteins Zebrafish Proteins axin1 protein, Xenopus beta Catenin Glycogen Synthase Kinases Calcium-Calmodulin-Dependent Protein Kinases Glycogen Synthase Kinase 3
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Fagotto F
Division of Cell Biology, Max-Planck Institute for Developmental Biology, 72076 Tübingen, Germany.
Jho E h
Zeng L
Kurth T
Joos T
Kaufmann C
Costantini F
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Article Info
Journal
The Journal of cell biology
Abbr.
J Cell Biol
ISSN
0021-9525
DOI
10.1083/jcb.145.4.741
Published
1999-05-17
Pages
741-56
Language
English
Region
United States
NLM ID
0375356
PMCID
PMC2133179
Subset
IM
Grants
NIGMS NIH HHS · GM56934 · United States
External Links
PubMed source DOI: 10.1083/jcb.145.4.741 PMC Full Text View journal details
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