Sonic hedgehog induces transcription-independent cytoskeletal rearrangement and migration regulated by arachidonate metabolites.

Sonic hedgehog (Shh) is a morphogen pivotal for development and tissue maintenance. Biological effects of Shh are mediated through a pathway that involves binding to patched1 (Ptch1), thereby releasing Smoothened (Smo) from inhibition resulting in the activation of Gli transcription factors, which mediate the induction of Shh target genes. Here, we describe a novel signal transduction pathway for Shh, which is transcription/translation-independent, SuFu insensitive, and consequently independent of Gli-mediated induction of transcription. Through this alternative pathway Shh, transduced via Smo, induced altered cell morphology together with lamellipodia formation. Migration assays demonstrate that this cytoskeletal rearrangement mediates the migratory response to Shh. This Shh-induced, Smo mediated migration utilizes and requires the metabolism of arachidonic acid through the 5-lipoxygenase pathway. These data provide a link between a seemingly novel Gli-independent Hh signaling pathway and the leukotriene metabolism, and might explain the developmental abnormalities observed in both patients with defective leukotriene metabolism as well as in rodent models of defective Rho family GTPase signaling.