Initiation of Wnt Frizzled Signaling

Wnt/Frizzled signaling has been extensively studied in embryogenesis and development of vertebrates and invertebrates.94 Wnt and its Frizzled receptor govern the

FIGURE 5.2 Simplified scheme of the Hedgehog and Frizzled signal transduction pathways. Patched (Ptc) is an inhibitor of the Smoothened (Smo) protein. In the absence of Hedgehog (Hh) protein-binding to Ptc, the transcription factor Ci is tethered to microtubules by Cos2 and Fused (Fu) proteins, allowing Ci to be cleaved into a transcriptional repressor to block transcription of particular genes. Hh binding to Ptc results in conformational changes and release of the inhibitory action on Smo. Most likely the constitutive activity of Smo then leads to phosphorylation of Cos2 and Fu and release of Ci from microtubules. Ci acts as a transcriptional activator of Hh-response genes, including genes encoding Wingless (Wnt) proteins, which are secreted and diffuse to surrounding cells to interact with Frizzled receptor-low density lipoprotein receptor-related protein (FzR-LPR) complexes. Binding of Wnt to FzR-LRP complexes antagonizes the actions of APC-Axin to stabilise b-catenin by recruitment of Disheveled (Dvl) proteins to FzRs. Accumulated b-catenin may enter the nucleus to bind to the TCF/LEF family of transcription factors to induce transcription of particular genes, including the genes encoding Hh proteins. Hh proteins diffuse from these cells to interact with Ptc receptors to induce Smo signaling. (See also text).

morphogenetic processes of gastrulation. Movement of cells during this process requires the cells to undergo transient transitions that allow them to dissociate and migrate. To this end, FzRs activate various intracellular signaling cascades that affect cellular processes including differentiation, proliferation, motility, and polarity. Cell dissociation and migration are also essential for tumor cell invasion and metastasis and accumulating evidence emphasizes the importance of Frizzled in tumor growth and progression.98

In the absence of a Wnt signal, the signal transduction pathway is off, resulting in the destruction of p-catenin by the proteosome. A large multiprotein complex that includes proteins of the APC (the tumor suppressor protein encoded by the adenom-alous polyposis coli (APC) gene) and Axin families normally facilitate the phosphorylation of p-catenin by glycogen synthase kinase-3p (GSK3p). Phosphorylated p-catenin is subsequently ubiquitinated and degraded by the proteosome. Binding of secreted Wnt proteins to dedicated FzR-low-density lipoprotein receptor-related protein complexes triggers the intracellular Wnt signaling cascade by antagonizing the actions APC-Axin via an unknown mechanism that requires the Dvl (Dishevelled) protein. In addition to the modulation of the TCF/LEF transcription factors, the recruitment of Dvl to FzRs may also serve to activate the small guanosine triphosphatase (GTPase) RhoA.

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