Smoothened Regulates Activator and Repressor Functions of Hedgehog Signaling via Two Distinct Mechanisms

Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, California, United States
Journal of Biological Chemistry (Impact Factor: 4.57). 04/2006; 281(11):7237-43. DOI: 10.1074/jbc.M510169200
Source: PubMed


The secreted protein Hedgehog (Hh) plays an important role in metazoan development and as a survival factor for many human
tumors. In both cases, Hh signaling proceeds through the activation of the seven-transmembrane protein Smoothened (Smo), which
is thought to convert the Gli family of transcription factors from transcriptional repressors to transcriptional activators.
Here, we provide evidence that Smo signals to the Hh signaling complex, which consists of the kinesin-related protein Costal2
(Cos2), the protein kinase Fused (Fu), and the Drosophila Gli homolog cubitus interruptus (Ci), in two distinct manners. We show that many of the commonly observed molecular events
following Hh signaling are not transmitted in a linear fashion but instead are activated through two signals that bifurcate
at Smo to independently affect activator and repressor pools of Ci.

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    • "To assess the efficacy of RNAi knockdown in the adult wing, we designed strains that target smo with RNAi. smo RNAi expressed under the control of ptc produced partial proximal fusions of longitudinal veins 3 and 4 near the anterior cross vein (Figure 1, A and B; Ogden et al. 2006). These fusions are similar to the defects that are observed with weak loss-of-function alleles of fused (fu), a gene that encodes a putative protein kinase that is required downstream of smo for Hh pathway activation. "
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    • "Intriguingly, a kinesin-like protein Costal-2 controls both positive and negative functions of hedgehog signalling in Drosophila (Kalderon, 2004). Costal-2 has been proposed to serve as a scaffold regulating the assembly and activity of two types of hedgehog signalling complexes (HSC), HSC-activator and HSC-repressor (Ogden et al., 2006). Both functions require direct binding of Costal-2 to the Gli homologue Cubitus interruptus (Ci) and Smoothened receptor and are regulated by multiple kinases. "
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