Purified Wnt5a Protein Activates or Inhibits β-Catenin–TCF Signaling Depending on Receptor Context

By Amanda J Mikels, R. Nusse. PLoS Biology, 2006

1,267 citations recorded by the source corpus.

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 β-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 β-catenin levels but by downregulating β-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 β-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.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/d6ce2210445f78f8b09e4d30696aa4f22b821d29

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Genetics

1. Hans Clevers
2. S. Angers
3. G. Schulte
4. J. Petersen
5. Christof Niehrs
6. J. Dijksterhuis
7. R. Nusse
8. Pengfei Lu

In Molecular Biology

1. Hans Clevers
2. Christof Niehrs
3. S. Angers
4. R. Daneman
5. G. Schulte
6. J. Petersen
7. J. Dijksterhuis
8. R. Moon

Citations in the corpus

• Wnt/beta-catenin signaling in development and disease. (2006, positive): “pathway, although paradoxically Wnt5a can also activate the canonical pathway by directly engaging Fz4 (Mikels and Nusse, 2006) and Fz5 (He et al.”
• INTERNATIONAL UNION OF BASIC AND CLINICAL PHARMACOLOGY REVIEW WNT/Frizzled signalling: receptor-ligand selectivity with focus on FZD-G protein signalling and its physiological relevance: IUPHAR Review 3 (2014, positive): “Further, WNT-5A triggers β-catenin signalling in HEK294/FZD4 cells, a response that can be inhibited when it is co-transfected with the receptor ROR2 (Mikels and Nusse, 2006).”
• Function and biological roles of the Dickkopf family of Wnt modulators (2006, background): “In addition to Fz and Lrp6, there are two other Wnt coreceptors, Ror2, an orphan tyrosine kinase possessing a CRD domain, which is bound by Wnt5a and activates JNK (Oishi et al., 2003; Mikels and Nusse, 2006), and the tyrosine kinase Derailed/Ryk (Yoshikawa et al., 2003).”
• Proximal events in Wnt signal transduction (2009, background): “Consistent with a role for Ror2 in the antagonism of β-catenin signalling, the ability of Wnt5a to block the Wnt3a -dependent activation of β-catenin signalling is strongly potentiated in human HEK293 cells that stably express mouse Ror2 (Ref”
• Wnt/β-catenin signaling is required for CNS, but not non-CNS, angiogenesis (2009, background): “These ligands may also be able to activate canonical -catenin signaling depending on the Frizzled receptor type(s) expressed by the endothelial cells (14).”