Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK.
1] University Nice Sophia Antipolis, iBV, UMR 7277, 06100 Nice, France [2] CNRS, iBV, UMR 7277, Parc Valrose, 06100 Nice, France [3] INSERM, iBV, U10891, 06100 Nice, France.
Nat Commun. 2014 Oct 7;5:5034. doi: 10.1038/ncomms6034.
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). Protein Kinase A (PKA)-dependent phosphorylation of the serpentine protein Smoothened (Smo) leads to Ci activation, whereas PKA-dependent phosphorylation of Ci leads to the formation of Ci repressor form. The mechanism that switches PKA from an activator to a repressor is not known. Here we show that Hh signalling activation causes PKA 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 PKA and causes a switch in PKA substrate recognition. We propose a new model in which the PKA 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.
刺猬（Hh）信号对于发育模式和组织内稳态至关重要。在果蝇中，Hh 信号由一种双功能转录调节剂——称为中断 Cubitus（Ci）介导。蛋白激酶 A（PKA）依赖性丝氨酸蛋白 Smoothened（Smo）磷酸化导致 Ci 激活，而 PKA 依赖性 Ci 磷酸化导致 Ci 抑制形式的形成。将 PKA 从激活剂切换为抑制剂的机制尚不清楚。在这里，我们表明 Hh 信号激活导致 PKA 在 Hh 信号复合物（HSC）中从 Ci 切换到 Smo 的底物。具体来说，Hh 信号增加了 Smo 的水平，然后 Smo 与 PKA 的结合竞争 Ci，导致 PKA 底物识别的转变。我们提出了一个新模型，其中 PKA 在 HSC 中持续存在并具有活性，并且 HSC 中 Ci 和 Smo 的相对水平决定了对 Hh 信号的不同激活和细胞反应。
