Phosphorylation of Gli by cAMP-dependent protein kinase

Hedgehog (Hh) signaling plays a central role in many developmental processes. Hh protein is a developmental morphogen that elicits a graded cellular response depending on the distance between the recipient cell and the ligand-secreting cell. Gli transcription factors are effectors that induce the expression of downstream target genes. The outline of this cascade from Hh to Gli has been elucidated, and many components have been identified. However, the interpretation of graded ligand stimulation remains to be resolved. Among the components, adenosine 3'5'-cyclic monophosphate-dependent protein kinase (PKA) functions as a negative regulator that phosphorylates a specific region of Gli, thereby inducing proteolytic cleavage to generate the repressor form. In addition, recent studies have identified different mechanisms that are followed by PKA phosphorylation of Gli. In this review, we examine Hh signaling and PKA phosphorylation and propose a possible interaction between the multiple mechanisms regulated by PKA and the gradient-dependent response.