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First published online January 27, 2006
doi: 10.1242/10.1242/jcs.02826

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Wnt signaling: complexity at the surface

Department of Molecular, Cellular and Developmental Biology, University of Michigan, Natural Science Building, Ann Arbor, MI 48109-1048, USA

View larger version (24K): [in a new window]   Fig. 1. Outline of Wnt/ß-catenin signaling. (A) In the absence of Wnt, ß-catenin (ß-cat) is phosphorylated by a complex containing GSK3. This targets ß-catenin for proteosomal degradation. In the nucleus, members of the T-cell factor (TCF) family of DNA-binding proteins repress Wnt targets, in concert with co-repressors such as Groucho (Gro). (B) Upon Wnt binding to Fz-LRP receptors, a combination of LRP-axin interaction and Dvl phosphorylation (P) blocks the APC-axin-GSK3 complex from phosphorylating ß-catenin. The accumulated ß-catenin then enters the nucleus, where it converts TCF into a transcriptional activator. See the Wnt homepage (http://www.stanford.edu/~rnusse/wntwindow.html) for a more complete description of Wnt signaling components.

View larger version (22K): [in a new window]   Fig. 2. The two-signal model of Fz-LRP signaling to ß-catenin showing the regulatory relationships between each component (A) and summarizing the probable physical interactions (B). In this model, Wnt stimulation promotes Fz-LRP oligomerization, which transduces two separate signals to the cytoplasm. The first signal is LRP phosphorylation, mediated by membrane-localized GSK3 and LRP-bound CKI. We speculate that neither kinase is activated by Wnt. Rather, the LPR-Wnt-Fz interaction allows LRP to become phosphorylatable, which then promotes the recruitment of axin to the plasma membrane, leading to its inactivation and/or degradation. The second signal is Fz-dependent Dsh/Dvl phosphorylation, which we tentatively propose involves trimeric G proteins. Activated Dvl then inhibits the APC-axin-GSK3 complex by a poorly understood mechanism. The dashed line in panel A reflects the fact that Dsh/Dvl also participates in recruitment of axin to the plasma membrane. Although hyperactivation of either branch by overexpression can stabilize ß-catenin, both signals are required under physiological conditions.

View larger version (12K): [in a new window]   Fig. 3. Outline of several Wnt signaling pathways. The Wnt/ß-catenin, PCP and Wnt/Ca2+ pathways are shown. All three require Fz-family members. Dsh/Dvl is required for both the ß-catenin and PCP pathways; its role in Wnt/Ca2+ signaling is less clear (see Veeman et al., 2003). LRP is thought to be specific for Wnt/ß-catenin signaling.

View larger version (24K): [in a new window]   Fig. 4. Three models for Ryk in Wnt signaling. (A) In Drosophila, Drl acts as a receptor for Wnt5 to mediate axonal guidance signaling (Yoshikawa et al., 2003). Whether Drl acts with a Fz and through ß-catenin is not clear. (B) In C. elegans vulva development, a Ryk (LIN-18) and Wnt (MOM-2) are thought to act in parallel to a Wnt-Fz pair (LIN-44–LIN17) to specify P7 cell fate (Inoue et al., 2004). The downstream signaling mechanism is not clear. (C) In human HEK-293T cells, Ryk is thought to act as a co-receptor for Fz8 to mediate Wnt/ß-catenin signaling (Lu et al., 2004).