Editors' ChoiceCell Biology

Shared Means to Distinct Ends

Science Signaling  23 Nov 2010:
Vol. 3, Issue 149, pp. ec356
DOI: 10.1126/scisignal.3149ec356

When a Wnt ligand simultaneously binds to its co-receptors Frizzled (Fzd) and low-density receptor–related protein (LRP), Fzd-associated intracellular components phosphorylate and activate LRP to trigger canonical Wnt–β-catenin signaling. It has been postulated that noncanonical Wnt signaling may be initiated by Wnt binding to other receptors, such as Ror2 or Ryk. Grumolato et al. report that, in various cultured human and rodent cell lines, application of either Wnt3a (canonical) or Wnt5a (noncanonical) activated the intracellular effector disheveled (Dvl), indicating that both ligands activated Fzd. However, Wnt3a stimulated phosphorylation of LRP5 and LRP6, and Wnt5a induced phosphorylation of Ror1 and Ror2. Fzd and its intracellular effectors Dvl, axin, and glycogen synthase kinase 3 (GSK3) were required for both Wnt3a-induced activation of LRPs and Wnt5a-induced activation of Ror2. Furthermore, GSK3, which phosphorylates LRP6 in canonical Wnt signaling, phosphorylated Ser864 of Ror2 in vitro, demonstrating that both Wnts used a common mechanism for activating their specific co-receptors. Whereas Wnt5a induced migration of cells carrying wild-type or kinase-dead Ror2, it failed to stimulate migration of cells containing a mutant form of Ror2 in which Ser864 had been changed to Ala, indicating that Wnt5a-inducd Ror2 activation depended on the ligand-induced interaction with Fzd and not on trans-autophosphorylation of Ror2. Wnt3a and Wnt5a competed for binding to Fzd in vitro, Wnt3a inhibited Wnt5-induced phosphorylation of Ror2, and Wnt5a inhibited Wnt3a-induced phosphorylation of LRP6. This mutual antagonism was also observed in assays using a human mesenchymal stem cell differentiation model. Thus, different Wnt ligands can activate distinct signaling pathways by stimulating unrelated co-receptors through a common mechanism.

L. Grumolato, G. Liu, P. Mong, R. Mudbhary, R. Biswas, R. Arroyave, S. Vijayakumar, A. N. Economides, S. A. Aaronson, Canonical and noncanonical Wnts use a common mechanism to activate completely unrelated coreceptors. Genes Dev. 24, 2517–2530 (2010). [Abstract] [Full Text]