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Purified Wnt5a protein activates or inhibits beta-catenin-TCF signaling depending on receptor context.
- Source :
-
PLoS biology [PLoS Biol] 2006 Apr; Vol. 4 (4), pp. e115. Date of Electronic Publication: 2006 Apr 04. - Publication Year :
- 2006
-
Abstract
- The Wnts comprise a large class of secreted proteins that control essential developmental processes such as embryonic patterning, cell growth, migration, and differentiation. In the most well-understood "canonical" Wnt signaling pathway, Wnt binding to Frizzled receptors induces beta-catenin protein stabilization and entry into the nucleus, where it complexes with T-cell factor/lymphoid enhancer factor transcription factors to affect the transcription of target genes. In addition to the canonical pathway, evidence for several other Wnt signaling pathways has accumulated, in particular for Wnt5a, which has therefore been classified as a noncanonical Wnt family member. To study the alternative mechanisms by which Wnt proteins signal, we purified the Wnt5a protein to homogeneity. We find that purified Wnt5a inhibits Wnt3a protein-induced canonical Wnt signaling in a dose-dependent manner, not by influencing beta-catenin levels but by downregulating beta-catenin-induced reporter gene expression. The Wnt5a signal is mediated by the orphan tyrosine kinase Ror2, is pertussis toxin insensitive, and does not influence cellular calcium levels. We show that in addition to its inhibitory function, Wnt5a can also activate beta-catenin signaling in the presence of the appropriate Frizzled receptor, Frizzled 4. Thus, this study shows for the first time that a single Wnt ligand can initiate discrete signaling pathways through the activation of two distinct receptors. Based on these and additional observations, we propose a model wherein receptor context dictates Wnt signaling output. In this model, signaling by different Wnt family members is not intrinsically regulated by the Wnt proteins themselves but by receptor availability.
- Subjects :
- Amino Acid Sequence
Animals
Calcium chemistry
Calcium metabolism
Cations, Divalent chemistry
Cell Line
Frizzled Receptors metabolism
Gene Expression Regulation
Humans
Mice
Molecular Sequence Data
Protein Processing, Post-Translational
Proto-Oncogene Proteins chemistry
Proto-Oncogene Proteins isolation & purification
Proto-Oncogene Proteins metabolism
Receptor Protein-Tyrosine Kinases metabolism
Receptor Tyrosine Kinase-like Orphan Receptors
Wnt Proteins chemistry
Wnt Proteins isolation & purification
Wnt Proteins metabolism
Wnt-5a Protein
Proto-Oncogene Proteins pharmacology
Signal Transduction drug effects
TCF Transcription Factors metabolism
Wnt Proteins pharmacology
beta Catenin metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1545-7885
- Volume :
- 4
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- PLoS biology
- Publication Type :
- Academic Journal
- Accession number :
- 16602827
- Full Text :
- https://doi.org/10.1371/journal.pbio.0040115