PUBLICATION

Protein encoded by the AxinFu allele effectively downregulates Wnt signaling but exerts a dominant negative effect on c-Jun N-terminal kinase signaling

Authors
Lu, Z., Liu, W., Huang, H., He, Y., Han, Y., Wang, Y., Li, Q., Ruan, K., Ye, Z., Low, B.C., Meng, A., and Lin, S.C.
ID
ZDB-PUB-080311-1
Date
2008
Source
The Journal of biological chemistry   283(19): 13132-13139 (Journal)
Registered Authors
Liu, Wei, Meng, Anming
Keywords
none
MeSH Terms
  • Alleles*
  • Animals
  • Axin Protein
  • Cell Line
  • Dimerization
  • Down-Regulation*
  • Enzyme Activation
  • Humans
  • JNK Mitogen-Activated Protein Kinases/genetics
  • JNK Mitogen-Activated Protein Kinases/metabolism
  • Mice
  • Mice, Transgenic
  • Mutation/genetics
  • Phenotype
  • Repressor Proteins/genetics
  • Repressor Proteins/metabolism*
  • Signal Transduction*
  • Wnt Proteins/metabolism*
  • Zebrafish/embryology
  • Zebrafish/genetics
  • Zebrafish/metabolism
PubMed
18316368 Full text @ J. Biol. Chem.
Abstract

Axin plays an architectural role in many important signaling pathways that control various aspects of development and tumorigenesis, including the Wnt, transforming growth factor-β, MAP kinase pathways, as well as p53 activation cascades. It is encoded by the mouse Fused (Fu) locus; the AxinFu allele is caused by insertion of an IAP transposon. AxinFu/Fu mice display varying phenotypes ranging from embryonic lethality to relatively normal adulthood with kinky tails. However, the protein product(s) has not been identified or characterized. In the present study, we conducted immunoprecipitation using brain extracts from the AxinFu mice with specific antibodies against different regions of Axin and found that a truncated Axin containing amino acids 1–596 (designated as AxinFu-NT) and the full-length complement of Axin (AxinWT) can both be generated from the AxinFu allele. When tested for functionality changes, AxinFu-NT was found to abolish Axin-mediated activation of JNK, which plays a critical role in dorsoventral patterning. Together with a proteomics approach, we found that AxinFu-NT contains a previously uncharacterized dimerization domain and can form a heterodimeric interaction with AxinWT. The AxinFu-NT/AxinWT is not conducive to JNK activation, providing a molecular explanation for the dominant negative effect of AxinFu-NT on JNK activation by wild-type Axin. Importantly, AxinFu-NT exhibits no difference in the inhibition of Wnt signaling compared with AxinWT as determined by reporter gene assays, interaction with key Wnt regulators, and expression of Wnt marker genes in zebrafish embryos, suggesting that altered JNK signaling contributes, at least in part, to the developmental defects seen in AxinFu mice.

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Human Disease / Model Data
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Orthology
Engineered Foreign Genes
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Errata and Notes