PKAc-directed interaction and phosphorylation of Ptc is required for Hh signaling inhibition in Drosophila.

Ptc is a gatekeeper to avoid abnormal Hh signaling activation, but the key regulators involved in Ptc-mediated inhibition remain largely unknown. Here, we identify as a key regulator required for Ptc inhibitory function. In the absence of Hh, duanyu1529c physically interacts with Ptc and phosphorylates Ptc at Ser-1150 and -1183 residues. The presence of Hh unleashes duanyu1529c from Ptc and activates Hh signaling. By combining both in vitro and in vivo functional assays, we demonstrate that such interaction and Ptc phosphorylation are both important for Ptc inhibitory function. Interestingly, we further demonstrate that duanyu1529c is subjected to palmitoylation, contributing to its kinase activity on plasma membrane. Based on those novel findings, we establish a working model on Ptc inhibitory function: In the absence of Hh, duanyu1529c interacts with and phosphorylates Ptc to ensure its inhibitory function; and Hh presence releases duanyu1529c from Ptc, resulting in Hh signaling activation.

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