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Membrane-anchored plakoglobins have multiple mechanisms of action in Wnt signaling
- Source :
- Scopus-Elsevier, ResearcherID
-
Abstract
- In Wnt signaling, beta-catenin and plakoglobin transduce signals to the nucleus through interactions with TCF-type transcription factors. However, when plakoglobin is artificially engineered to restrict it to the cytoplasm by fusion with the transmembrane domain of connexin (cnxPg), it efficiently induces a Wnt-like axis duplication phenotype in Xenopus. In Xenopus embryos, maternal XTCF3 normally represses ventral expression of the dorsalizing gene Siamois. Two models have been proposed to explain the Wnt-like activity of cnxPg: 1) that cnxPg inhibits the machinery involved in the turnover of cytosolic beta-catenin, which then accumulates and inhibits maternal XTCF3, and 2) that cnxPg directly acts to inhibit XTCF3 activity. To distinguish between these models, we created a series of N-terminal deletion mutations of cnxPg and examined their ability to induce an ectopic axis in Xenopus, activate a TCF-responsive reporter (OT), stabilize beta-catenin, and colocalize with components of the Wnt signaling pathway. cnxPg does not colocalize with the Wnt pathway component Dishevelled, but it does lead to the redistribution of APC and Axin, two proteins involved in the regulation of beta-catenin turnover. Expression of cnxPg increases levels of cytosolic beta-catenin; however, this effect does not completely explain its signaling activity. Although cnxPg and Wnt-1 stabilize beta-catenin to similar extents, cnxPg activates OT to 10- to 20-fold higher levels than Wnt-1. Moreover, although LEF1 and TCF4 synergize with beta-catenin and plakoglobin to activate OT, both suppress the signaling activity of cnxPg. In contrast, XTCF3 suppresses the signaling activity of both beta-catenin and cnxPg. Both exogenous XLEF1 and XTCF3 are sequestered in the cytoplasm of Xenopus cells by cnxPg. Based on these data, we conclude that, in addition to its effects on beta-catenin, cnxPg interacts with other components of the Wnt pathway, perhaps TCFs, and that these interactions contribute to its signaling activity.
- Subjects :
- Models, Molecular
Beta-catenin
Xenopus
Plakoglobin
Fluorescent Antibody Technique
Wnt1 Protein
Biology
Xenopus Proteins
Connexins
Article
Cell Line
Axin Protein
Genes, Reporter
Proto-Oncogene Proteins
Animals
Humans
Molecular Biology
Transcription factor
beta Catenin
Sequence Deletion
chemistry.chemical_classification
Homeodomain Proteins
Wnt signaling pathway
Proteins
Cell Biology
Intracellular Membranes
Zebrafish Proteins
biology.organism_classification
Cadherins
Dishevelled
Cell biology
Repressor Proteins
Wnt Proteins
Cytoskeletal Proteins
chemistry
Desmoplakins
biology.protein
Trans-Activators
gamma Catenin
Signal transduction
Plasmids
Signal Transduction
Transcription Factors
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Scopus-Elsevier, ResearcherID
- Accession number :
- edsair.doi.dedup.....434b94d59ae321aed66130ab4ef468ee