Editors' ChoiceWnt signaling

Putting β-Catenin on the Rac

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Science Signaling  22 Apr 2008:
Vol. 1, Issue 16, pp. ec148
DOI: 10.1126/stke.116ec148

Canonical Wnt signaling results in the stabilization and nuclear translocation of β-catenin, which activates the transcription of Wnt-responsive genes; however, the mechanism involved is poorly understood. Noting that Rho family guanosine triphosphatases (GTPases) mediate noncanonical Wnt signaling, Wu et al. examined the effects of Wnt3a (canonical) on Rho GTPase activation in a murine bone marrow stromal cell line. Western blot analyses showed that Wnt3a stimulated the accumulation of activated (GTP-bound) Rac1. Small inhibitory RNA (siRNA) specific for Rac1 reduced Wnt3a-induced activity of a reporter plasmid compared with that in control siRNA-treated cells. Cell fractionation experiments and confocal microscopy showed that dominant-negative Rac1 (dnRac1) blocked Wnt3a-dependent nuclear accumulation of β-catenin but not stabilization of cytosolic β-catenin. Inhibitor and siRNA experiments showed that Wnt3a-stimulated Rac1 activation required phosphoinositide 3-kinase (PI3K) activity. Wnt3a stimulated the phosphorylation and activation of c-Jun N-terminal kinase 2 (JNK2), which was blocked by dnRac1. An inhibitor of JNK or JNK-specific siRNA blocked Wnt3a-stimulated reporter activity and nuclear translocation of β-catenin. Coimmunoprecipitation experiments showed that Rac1, JNK2, and β-catenin constitutively formed a complex in the cytosol and that Wnt3a treatment resulted in the incorporation of phosphorylated JNK2 in this complex. In vitro kinase assays showed that JNK2 phosphorylated β-catenin. Deletion of Rac1 in the embryonic limb bud resulted in complete loss of the hindlimb and in various truncations of the forelimb in mouse embryos, a phenotype identical to that in mice with deletion of β-catenin in the same location. Together, these data suggest that canonical Wnt signaling activates a PI3K-Rac1-JNK2 pathway to phosphorylate β-catenin and mediate its translocation to the nucleus.

X. Wu, X. Tu, K. S. Joeng, M. J. Hilton, D. A. Williams, F. Long, Rac1 activation controls nuclear localization of β-catenin during canonical Wnt signaling. Cell 133, 340-353 (2008). [PubMed]

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