Altered localization ofDrosophilaSmoothened protein activates Hedgehog signal transduction

Abstract

Supplemental material is available at http://www.genesdev.org.

Regulation of Hedgehog signaling: a complex story

“…These results suggest that localization of Smo to the PM is a requisite step for functional signaling. Consistent with this argument, Smo targeted to the PM via a lipid anchor triggers activation of Hh target genes in a Hh independent manner [44]. It is not clear how Hh-stimulated PM localization of Smo allows for activation of the signaling cascade.…”

“…Both stabilization and phosphorylation appear to be actively repressed by Ptc, as these Smo modifications can occur in response to Ptc dysfunction or loss [39,42,43]. Conversely, over-expression of Ptc reduces Smo concentration and phosphorylation in both embryos and wing discs [39,43,44]. Ptc appears to function catalytically in repression and destabilization of Smo, as Ptc can block Smo signaling at substochiometric levels [45].…”

“…In cells not receiving Hh, Smo localizes to discrete endosomal vesicles, where it is believed to be degraded [39,47]. In response to Hh, Smo moves from internal structures to the plasma membrane (PM), presumably to activate the signaling cascade [39,44,47]. These results suggest that localization of Smo to the PM is a requisite step for functional signaling.…”

“…KRPs bind vesicular membranes and microtubules (MT) in a highly regulated manner, and can facilitate movement along MTs through ATP hydrolysis (reviewed in [77]). Although ATPase activity by Cos2 has yet to be demonstrated, evidence supporting Cos2-mediated transport activity in Hh signaling is growing [44,76,78]. Studies using Drosophila salivary glands as a model system demonstrated that over-expression of Cos2 resulted in redistribution of Smo from the plasma membrane to discrete intracellular vesicles in a MT-dependent manner [44].…”

“…Although ATPase activity by Cos2 has yet to be demonstrated, evidence supporting Cos2-mediated transport activity in Hh signaling is growing [44,76,78]. Studies using Drosophila salivary glands as a model system demonstrated that over-expression of Cos2 resulted in redistribution of Smo from the plasma membrane to discrete intracellular vesicles in a MT-dependent manner [44]. Expression of exogenous Hh in the presence of over-expressed Cos2 could trigger movement of Smo from vesicles to the PM [44].…”