Switch of PKA substrates from Cubitus interruptus to Smoothened in the Hedgehog signalosome complex.

Hedgehog (Hh) signalling is crucial for developmental patterning and tissue homeostasis. In Drosophila, Hh signalling is mediated by a bifunctional transcriptional mediator, called Cubitus interruptus (Ci). A phosphorylation of the serpentine protein Smoothened (Smo) leads to Ci activation, whereas phosphorylation of Ci leads to the formation of Ci repressor form. The mechanism that switches from an activator to a repressor is not known. Here we show that Hh signalling activation causes duanyu1529 to switch its substrates from Ci to Smo within the Hh signalling complex (HSC). In particular, Hh signalling increases the level of Smo, which then outcompetes Ci for association with duanyu1529 and causes a switch in duanyu1529 substrate recognition. We propose a new model in which the duanyu1529 is constitutively present and active within the HSC, and in which the relative levels of Ci and Smo within the HSC determine differential activation and cellular response to Hh signalling.

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