Variations in Hedgehog signaling: divergence and perpetuation in Sufu regulation of Gli

Abstract

The Hedgehog (Hh) proteins play a universal role in metazoan development. Nevertheless, fundamental differences exist between Drosophila and vertebrates in the transduction of the Hh signal, notably regarding the role of primary cilia in mammalian cells. In this issue of Genes & Development, Chen and colleagues (pp. 1910-1928) demonstrate that mouse Suppressor of fused (Sufu) regulates the stability of the transcription factors Gli2 and Gli3 by antagonizing the conserved Gli degradation device mediated by Hib/Spop in a cilia-independent manner.

Figure 1.

Stabilization, degradation, and activation of the Ci/Gli proteins by the Hh signaling pathway. (A) In Drosophila, the absence of Hh allows Ptc to inhibit Smo activity, and full-length Ci (Ci) activity is regulated by three different mechanisms, including phosphorylation, proteolysis, and stabilization. First, phosphorylation of Ci by multiple kinases, including PKA, targets Ci to the ubiquitin/proteasome-mediated partial proteolysis to generate a truncated repressor form of Ci (Ci-R). This step requires the kinesin-like protein Cos2, which acts as a molecular scaffold to bridge Ci and the kinases. Second, the activity of full-length Ci is also blocked by stoichiometric binding of Sufu, but is protected from Hib-dependent degradation. Third, the excess of Ci is controlled by Hib protein, which binds and completely degrades the full-lengh form of Ci. (B) Binding of Hh to Ptc stimulates Smo phosphorylation, which increases Smo cell surface concentration. The activation of Smo stimulates the associated Fu kinase activity and dissociates Ci from the Cos2 complex. This blocks PKA phosphorylation of Ci and subsequent processing. The Fu/Cos2 complex is also necessary to form the active Ci (Ci-A), but the mechanism of this activation, as its regulation by Sufu, is uncertain. (C) In mammals, in the absence of Hh, Ptc is present in the primary cilium and prevents Smo ciliary accumulation. PKA and others kinases phosphorylate Gli and target it for partial degradation to form the truncated repressor form of Gli (Gli-R). It is possible that the scaffolding role of Cos2 in Drosophila might have been replaced by the primary cilia. Independently of cilia, in the cytoplasm, the activity of full-length Gli is further blocked by Sufu, which appears to be the major mechanism for restricting Gli activity in mammals. In addition, Sufu protects Gli2 and Gli3 (but not Gli1) from degradation by Spop, the Hib mammalian homolog. (D) Binding of Hh to Ptc promotes the accumulation and activation of Smo in the cilium. Gli phosphorylation and processing are inhibited, and formation of the transcriptionally activated Gli (Gli-A) is triggered. This activation occurs in the cilia, but can also take place when both primary cilia and Sufu are lacking. The mechanism of Gli activation and Sufu regulation by Shh are not known. In both Drosophila and mammals, Sufu likely plays an important role in the nucleus, not indicated here.