Fig. 3.

Multiple kinases-phosphatases mediated progressive Smo phosphorylations interpret morphogenic Hh signals in signal-receiving cells. In response to Hh concentration gradient, Drosophila Smo exhibits graded phosphorylation status, which correspondingly activates the expressions of a series of target genes, such as dpp and ptc, responding to low-to-intermediate threshold, or high threshold Hh signals, respectively. The transcription effector Ci is switched from a repressor form CiR to an activator form CiA, triggering the expression of Hh target genes. During these progressive Smo phosphorylations, PKA and CK1 sequentially phosphorylate Smo, which promotes Smo accumulation on plasma membrane and facilitates Smo further phosphorylations by Gprk2 and Gish, two kinases preferring the distribution near plasma membrane, to achieve maximal activation of Smo. It has been known that PP1 and PP2A respectively counteract with PKA and CK1 to modulate Smo phosphorylation status. However, the phosphatase against Gprk2 or Gish has not been identified yet