title: Protein encoded by the Axin(Fu) allele effectively down-regulates Wnt signaling but exerts a dominant negative effect on c-Jun N-terminal kinase signaling.
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-beta, MAP kinase pathways, as well as p53 activation cascades. It is encoded by the mouse Fused (Fu) locus; the Axin(Fu) allele is caused by insertion of an IAP transposon. Axin(Fu/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 Axin(Fu) mice with specific antibodies against different regions of Axin and found that a truncated Axin containing amino acids 1-596 (designated as Axin(Fu-NT)) and the full-length complement of Axin (Axin(WT)) can both be generated from the Axin(Fu) allele. When tested for functionality changes, Axin(Fu-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 Axin(Fu-NT) contains a previously uncharacterized dimerization domain and can form a heterodimeric interaction with Axin(WT). The Axin(Fu-NT)/Axin(WT) is not conducive to JNK activation, providing a molecular explanation for the dominant negative effect of Axin(Fu-NT) on JNK activation by wild-type Axin. Importantly, Axin(Fu-NT) exhibits no difference in the inhibition of Wnt signaling compared with Axin(WT) 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 Axin(Fu) mice.
authors.affiliation: School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
authors.forename: Zailian
authors.initials: Z
authors.lastname: Lu
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Huizhe
authors.initials: H
authors.lastname: Huang
authors.forename: Ying
authors.initials: Y
authors.lastname: He
authors.forename: Ying
authors.initials: Y
authors.lastname: Han
authors.forename: Yanning
authors.initials: Y
authors.lastname: Rui
authors.forename: Yanhai
authors.initials: Y
authors.lastname: Wang
authors.forename: Qinxi
authors.initials: Q
authors.lastname: Li
authors.forename: Ka
authors.initials: K
authors.lastname: Ruan
authors.forename: Zhiyun
authors.initials: Z
authors.lastname: Ye
authors.forename: Boon Chuan
authors.initials: BC
authors.lastname: Low
authors.forename: Anming
authors.initials: A
authors.lastname: Meng
authors.forename: Sheng-Cai
authors.initials: SC
authors.lastname: Lin
mesh_terms: D000483:Alleles; D000818:Animals; D060466:Axin Protein; D002460:Cell Line; D019281:Dimerization; D015536:Down-Regulation; D004789:Enzyme Activation; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism*; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000378:metabolism
chemical_list: D060466:Axin Protein; D012097:Repressor Proteins; D051153:Wnt Proteins; D048031:JNK Mitogen-Activated Protein Kinases