The Wnt/beta-catenin signal transduction pathway plays a critical role in axis formation and head versus trunk induction during early vertebrate embryogenesis. This pathway also plays a pivotal role in human carcinogenesis, because several key Wnt signaling components are encoded by human oncogenes or tumor suppressor genes. To elucidate how the extracellular Wnt ligand stimulates intracellular signaling, we recently demonstrated that members of the LDL receptor-related protein (LRP) family, LRP5 and LRP6 (which are homologues of the Drosophila Arrow protein that are required for Wingless signaling), function as Wnt co-receptors for the seven-pass transmembrane Frizzled (Fz) receptor family. Wnt signaling induces a complex formation between Fz and LRP5/6. We further identified the head inducer Dickkopf-1 (Dkk-1) as a high affinity ligand for LRP5/6. Dkk-1 binding to LRP5/6 prevents Fz-LRP5/6 complex formation induced by Wnt. Dkk-1 function in head induction strictly correlates with its ability to bind LRP6 and to disrupt the Fz-LRP5/6 association.

Beta-catenin is a key output of Wnt signaling. Wnt stabilizes beta-catenin protein by preventing its phosphorylation-dependent degradation. We found that beta-Trcp, an F-box/WD40-repeat protein specifically recognizes phosphorylated beta-catenin and couples its phosphorylation to degradation. We recently also discovered a dual-kinase system for beta-catenin phosphorylation: CKI phosphorylation of beta-catenin precedes and is required for subsequent GSK-3 phosphorylation of beta-catenin. This dual-kinase mechanism provided insight into the molecular basis of beta-catenin mutations in human cancers.

Wnt signaling also controls cell polarity and movements during vertebrate gastrulation via a distinct signaling pathway that requires the Fz receptor but neither the LRP5/6 co-receptor nor beta-catenin. We found that a key output of this Wnt pathway is the Rho GTPase, a critical regulator of cytoskeleton structures. We also identified a novel protein, Daam1, which mediates Wnt/Fz activation of Rho and is essential for Xenopus embryo gastrulation.

In addition to our effort in the above areas, we are continuing in the identification of key components in different Wnt signaling pathways, and in understanding the mechanism by which the Wnt signaling specificity is governed. We are also studying, via functional expression screening and other cell biological methods, the mechanism of early neural development, and Wnt regulation in the central nervous system.

References

Tamai K, Semenov M, Kato Y, Spokony R, Liu C, Katsuyama Y, Hess F, Saint-Jeannet J-P, He X. (2000). LDL receptor-related proteins in Wnt signal transduction. Nature 407, 530-535.

Semenov M, Tamai K, Brott B, Kuhl M, Sokol S, He X. (2001) Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6. Current Biology 11: 951-961.

Habas R, Kato Y, He X. (2001). Wnt/Frizzled activation of Rho regulates vertebrate gastrulation and requires a novel Formin homology protein Daam1. Cell 107, 843-854.

Liu C, Li Y, Semenov M, Baeg G-H, Han C, Tan Y, Zhang Z, Lin X, He X. (2002), Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell 108, 837-847.

Kato Y, Habas R, Katsuyama Y, Naar, A, He X. (2002). A component of the ARC/Mediator complex required for TGF-beta/Nodal signaling. Nature, in the press.