Fig. 2. Overview of the Shh, TGFß/BMP and Wnt morphogenic signaling pathways. (A) Shh signaling pathway. Genetic and biochemical experiments have shown that Hhs activate signaling by binding to their receptor Patched (Ptc; a 12-pass transmembrane protein), which leads to the relief of Ptc-mediated inhibition of Smoothened (Smo), a seven-pass transmembrane (7TM) protein, which can then activate downstream signaling. Smo associates directly with a Ci-containing complex, which contains the atypical kinesin Costal 2 (Cos2), the protein kinase Fused (Fu) and the Suppressor of Fused [Su(fu)]. This complex constitutively suppresses pathway activity by leading to the proteolytic cleavage of Ci, which acts as a transcriptional repressor. Activation of Hh signaling reverses this regulatory effect and leads to the production of full-length Ci, which activates transcription of Hh target genes. (B) TGFß/BMP signaling pathway. Members of the Dpp/BMP/TGFß family regulate cell fate by inducing the dimerization of type I and type II TGFß receptors, resulting in phosphorylation and activation of the intracellular kinase domain of the type I receptor. Targets of the type I receptor are the receptor-regulated Smads (R-Smads) which, upon phosphorylation, associate with co-Smads and translocate to the nucleus where, together with DNA-binding partners such as Fast1, they activate transcription. (C) Wnt signaling pathway. Wnt ligands can activate several different signal transduction pathways. The canonical Wnt pathway controls gene expression by stabilizing ß-Catenin (ß-Cat). Frizzled (Fz) proteins are 7TM molecules that together with the low-density lipoprotein (LDL) receptor-related protein 5 and 6 (LRP5/6; Arrow in Drosophila) family of co-receptors, function as Wnt receptors. When Wnts are absent, ß-Catenin is phosphorylated by GSK3ß, leading to its proteasomal degradation. This process requires the formation of a complex scaffolded by Axin and adenomatous polyposis coli (Apc). Binding of Wnts to their receptors results in Dishevelled (Dsh) activation and suppression of GSK3ß activity, thus protecting ß-Catenin from degradation. Accumulated ß-Catenin converts the lymphoid enhancer factor (Lef)/Tcf from a transcriptional repressor to an activator. Two non-canonical Wnt pathways are: the Wnt/Ca²⁺ pathway and the planar cell polarity (PCP) pathway. The PCP pathway involves a non-canonical, ß-Catenin-independent, Wnt/Fz pathway that requires Dsh. A Wnt ligand for this pathway has yet to be identified in Drosophila, but Wnt ligands can activate an analogous pathway in vertebrates. The Wnt/Ca²⁺ pathway probably signals via heterotrimeric G-proteins (, ß and subunits) to mobilize intracellular Ca²⁺ and, in some contexts, to stimulate protein kinase C (PKC). In vertebrates, Wnt/Ca²⁺ signaling is activated by the same ligands as the PCP pathway, suggesting that these pathways might overlap.