Protein kinase A

Protein kinase A: Two Ways to Stop Hedgehog Signaling

Science's STKE  16 Nov 1999:
Vol. 1999, Issue 8, pp. tw2
DOI: 10.1126/stke.1999.8.tw2

The Hedgehog (Hh) family of secreted proteins controls cell growth and patterning during development, in part by regulating the expression of certain target genes in local areas. The effects of Hh are mediated through its receptor, Ptc, and the transcription factor Cubitus interruptus (Ci). In Drosophila wing development, full-length Ci functions as a transcriptional activator, but a cleaved form of Ci represses the expression of other target genes. It is thought that Ci is phosphorylated by protein kinase A (PKA) and that processing of Ci into a cleaved form involves Slimb, a protein which may specify phosphorylated targets for ubiquitin/proteosome proteolysis. Wang et al. show that in the developing Drosophila wing, phosphorylation of Ci by PKA not only signals for proteolytic processing but also blocks the ability of full-length Ci to activate transcription. Mutation of the cleavage site in Ci resulted in protein that was still phosphorylated by PKA in vivo, but whose activity was inhibited. This suggests that phosphorylation of full-length Ci by PKA may block the activator form of Ci, independent of the processing of Ci into its transcription-repressor form. The mechanisms by which phosphorylation regulates proteolysis of Ci or Ci activity remain to be determined.

Wang, G., Wang, B., and Jiang, J. (1999) Protein kinase A antagonizes Hedgehog signaling by regulating both the activator and repressor forms of Cubitus interruptus. Genes Dev. 13: 2828-2837. [Abstract] [Full Text]