The Wnt signaling pathway has important roles in regulating many biological processes during development and is also implicated in the behavior of some cancer cells (see the Perspective by Berndt and Moon). Cruciat et al. describe the mechanism of action of a protein found in a screen for proteins that influence Wnt signaling. DDX3, a DEAD box RNA helicase, is required for proper Wnt signaling in Xenopus laevis and Caenorhabditis elegans. It appears to act not through its action as an RNA helicase or through ATP binding but rather by interacting with and prompting the activation of the ε isoform of the protein kinase casein kinase 1 (CK1ε). In the Wnt pathway, CK1 family members stabilize the transcription factor β-catenin by phosphorylating the scaffold protein disheveled (DVL), thus inhibiting activity of the β-catenin destruction complex. Huang et al. investigated the function of receptor-interacting protein kinase 4 (RIPK4), the product of a gene that, when mutated, causes severe developmental defects in mice and humans. Overexpression of RIPK4 in cultured human cells activated transcription of genes regulated by the Wnt signaling pathway, and loss of RIPK4 function inhibited Wnt signaling in Xenopus embryos. At the molecular level, RIPK4 interacted with the Wnt co-receptor LRP6 and the Wnt signaling adaptor protein DVL2 and promoted phosphorylation of DVL2. Habib et al. demonstrated that LRP6 and other Wnt signaling components accumulated on the sides of mouse embryonic stem (ES) cells in contact with a bead on which recombinant mouse WNT3a was immobilized. As ES cells in contact with Wnt3a beads divided, the plane of division was oriented perpendicular to the bead in the majority of mitotic cells. After division, Wnt signaling components remained concentrated in the daughter cell proximal to the bead, which retained stem cell–like characteristics, and were comparatively reduced in the daughter cell distal to the bead, which showed gene expression patterns characteristic of differentiation. These in vitro findings are consistent with previous in vivo observations of a correlation between asymmetric distribution of Wnt receptors and asymmetric cell division in nematodes, suggesting that Wnt proteins could act as stem cell niche signals that allow for the production of differentiating daughter cells while maintaining the stem cell population.
C.-M. Cruciat, C. Dolde, R. E. A. de Groot, B. Ohkawara, C. Reinhard, H. C. Korswagen, C. Niehrs, RNA helicase DDX3 is a regulatory subunit of casein kinase 1 in Wnt–β-catenin signaling. Science 339, 1436–1441 (2013). [Abstract] [Full Text]
X. Huang, J. C. McGann, B. Y. Liu, R. N. Hannoush, J. R. Lill, V. Pham, K. Newton, M. Kakunda, J. Liu, C. Yu, S. G. Hymowitz, J.-A. Hongo, A. Wynshaw-Boris, P. Polakis, R. M. Harland, V. M. Dixit, Phosphorylation of Dishevelled by protein kinase RIPK4 regulates Wnt signaling. Science 339, 1441–1445 (2013). [Abstract] [Full Text]
S. J. Habib, B.-C. Chen, F.-C. Tsai, K. Anastassiadis, T. Meyer, E. Betzig, R. Nusse, A localized Wnt signal orients asymmetric stem cell division in vitro. Science 339, 1445–1448 (2013). [Abstract] [Full Text]