Wnt5a Goes Both Ways

Science's STKE  11 Apr 2006:
Vol. 2006, Issue 330, pp. tw119
DOI: 10.1126/stke.3302006tw119

The Wnt family of protein ligands have essential roles in regulating development and tumorigenesis, but their signaling mechanisms are still controversial and not well understood. Mammalian Wnts have 19 homologs, and some, in particular the Wnt5a group, have distinct actions in development. Mikels and Nusse explored the signaling mechanisms that account for this behavior. They used purified mouse Wnt5a protein to stimulate 293 cells carrying a reporter gene to monitor Wnt-induced transcription. Wnt5a by itself had no effect, but it inhibited Wnt3a-activated transcription. Wnt5a did not interfere with early signaling events initiated by Wnt3a that lead to accumulation of β-catenin and its transport to the nucleus. Rather, the inhibitory effects of Wnt5a depended on its interaction with Ror2, a receptor tyrosine kinase that functions as a Wnt receptor (in addition to the usual Frizzled receptor proteins that are the most studied mediators of Wnt signaling). In 293 cells overexpressing Ror2, the inhibitory effect of Wnt5a on Wnt3a signaling was enhanced, and the inhibitory effects of Wnt5a were lost in cells expressing a mutant form of Ror2 that could not bind Wnt5a. Part of the confusion in the literature on Wnt5a has to do with whether it can activate as well as inhibit Wnt signaling. Mikels and Nusse confirmed that, in their cell system, Wnt5a could indeed stimulate reporter gene transcription if the cells stably expressed the Frizzled 4 receptor protein. The authors liken versatility to produce opposite signaling outcomes to that of Netrins, another set of protein ligands that can attract or repel axons depending on the receptor repertoire expressed on the axon. Furthermore, the authors propose that distinct Wnt5a signaling mechanisms they have studied may account for Wnt5a's implication as both an oncogene and tumor suppressor, depending on which paper you might be reading.

A. J. Mikels, R. Nusse, Purified Wnt5a protein activates or inhibits β-catenin-TCF signaling depending on receptor context. PLoS Biol. 4, e115 (2006) [PubMed]