Does Hedgehog Utilize Multiple Routes?

Abstract

Hedgehog (Hh), a secreted protein that regulates tissue patterning during development, binds to its receptor to activate Smoothened (Smo) and thereby initiates a signaling cascade that leads to transcriptional activation of target genes. In the absence of Hh signaling, the Drosophila transcription factor cubitus interruptus (Ci) is converted through proteolytic processing into Ci 75 , which acts as a transcriptional repressor. Hh signals through Smo to the Hh signaling complex [HSC, which contains Costal2 (Cos2) and Fused (Fu) as well as Ci] to inhibit conversion of Ci to Ci 75 and promote activation of Ci into a transcriptional activator. Smo interacts with Cos2 through the Cos2 carboxyl-terminal Smo binding domain (CSBD), and Ogden et al. found that overexpression of CSBD in Clone-8 cells inhibited Hh-mediated activation of a target gene, as did a construct expressing the Smo carboxyl-terminal tail (SmoC). However, SmoC also inhibited Hh-mediated Fu and Cos2 phosphorylation and Hh's stabilization of full-length Ci, whereas CSBD did not. Moreover, although the phenotype of transgenic flies expressing CSBD in wing imaginal discs was consistent with disruption of Hh signaling and expression of genes activated by Ci was decreased, Ci abundance, and expression of a gene whose transcription depends only on the loss of Ci 75 repression, was not affected. CSBD did not affect Hh-dependent release of the HSC from membranes in cultured cells but did inhibit Hh-dependent Smo stabilization, phosphorylation, and translocation to the plasma membrane. Thus, the authors propose that Hh and Smo regulate Ci activation independently of their inhibition of Ci 75 production rather than through a linear signaling pathway. S. K. Ogden, D. J. Casso, M. Ascano Jr., M. M. Yore, T. B. Kornberg, D. J. Robbins, Smoothened regulates activator and repressor functions of Hedgehog signaling via two distinct mechanisms. J. Biol. Chem. 281 , 7237-7243 (2006). [Abstract] [Full Text]