Suppressor of Fused opposes Hedgehog signal transduction by impeding nuclear accumulation of the activator form of Cubitus interruptus

Hedgehog controls the expression of key developmental genes through the conversion of the transcription factor Cubitus interruptus (Ci) into either an activator (Ciact) or a repressor (Cirep) form. Proteolytic cleavage of full-length Ci is important for the generation of Cirep, but little is known about how Ciact arises in response to Hh. Here we examine Hh signal transduction components for their role in the conversion of full-length Ci into either Ciact or Cirep. We report that Cos2, PKA and Fused are necessary for the generation of Cirep, whereas the inhibition of either Cos2 or PKA activity is a prerequisite for Ciact formation. Fused (Fu) kinase stimulates a constitutively active form of Ci in a Hh-dependent manner, suggesting that Fu enhances the activity rather than the formation of Ciact. Su(fu) reduces the nuclear accumulation of the constitutively active form of Ci, arguing that Su(fu) can function subsequent to Ciact formation. We propose that Hh induces target gene expression by a two-step mechanism in which Ciact is first formed and then accumulates in the nucleus via Fu-induced neutralization of Su(fu) activity.