Hedgehog (Hh) signalling, which mediates many important developmental processes, is regulated by the phosphorylation state of both the seven-transmembrane protein Smoothened (Smo) and the Zn-finger transcription factor Ci/Gli. In Drosophila, multiple kinases are involved in Smo and Ci phosphorylation. Now, Jia and co-workers report that the serine/threonine protein phosphatases PP4 and PP2A also regulate Hh signalling by controlling Smo and Ci dephosphorylation, respectively (see ). By examining wing development, they show that RNAi knockdown of PP4 increases Smo phosphorylation and accumulation, which leads to increased Hh signalling activity. Other experiments suggest that Hh normally promotes Smo phosphorylation, at least in part, by downregulating the Smo-PP4 interaction,which is mediated by the kinesin-related protein Costal 2. The researchers also provide evidence that PP2A is a Ci phosphatase and that it upregulates the signalling activity of full-length Ci, the form of Ci that activates Hh target genes. Thus, they conclude, multiple phosphatases - as well as multiple kinases - regulate the Hh signalling cascade.
