Research ArticleDevelopment

Sequential Phosphorylation of Smoothened Transduces Graded Hedgehog Signaling

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Science Signaling  05 Jul 2011:
Vol. 4, Issue 180, pp. ra43
DOI: 10.1126/scisignal.2001747

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It Takes Two (and Two)

Signaling by gradients of the morphogen Hedgehog (Hh) is required for the proper patterning of cells in the developing Drosophila wing. In the absence of Hh, its receptor Patched (Ptc) inhibits another membrane-bound protein known as Smoothened (Smo), and this results in cleavage of the transcription factor Cubitus interruptus (Ci) to generate a transcriptional repressor. When Hh binds to Ptc, however, inhibition of Smo is relieved, and uncleaved Ci translocates to the nucleus to drive target gene expression. Noting that phosphorylation of a cluster of sites in the cytoplasmic tail of Smo that are targeted by the kinases PKA and CKI regulates the cell surface localization of Smo, Su et al. investigated roles for phosphatases in regulating Smo signaling. They found that low concentrations of Hh resulted in PKA-mediated phosphorylation of Smo, whereas enhanced Hh signaling led to the additional phosphorylation of Smo by CKI. Furthermore, PKA-phosphorylated sites in Smo were targeted by the phosphatase PP1, whereas CKI-phosphorylated sites were dephosphorylated by PP2A. Thus, the authors propose that the composition of phosphorylated residues in Smo and the combined activities of phosphatases enable cells to convert graded Hh concentrations into graded Hh-dependent signals.