Price Mary Ann, Kalderon Daniel
Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
Cell. 2002 Mar 22;108(6):823-35. doi: 10.1016/s0092-8674(02)00664-5.
The secreted signaling molecule Hedgehog regulates gene expression in target cells in part by preventing proteolysis of the full-length Cubitus interruptus (Ci-155) transcriptional activator to the Ci-75 repressor form. Ci-155 proteolysis depends on phosphorylation at three sites by Protein Kinase A (PKA). We show that these phosphoserines prime further phosphorylation at adjacent Glycogen Synthase Kinase 3 (GSK3) and Casein Kinase I (CK1) sites. Alteration of the GSK3 or CK1 sites prevents Ci-155 proteolysis and activates Ci in the absence of Hedgehog. Ci-155 proteolysis is also inhibited if cells lack activity of the Drosophila GSK3, Shaggy, previously implicated in Wingless signaling. Conversely, Ci-155 levels are reduced in Hedgehog-responding cells by overexpression of PKA and the Drosophila CK1, Double-time, a regulator of circadian rhythms.
分泌型信号分子刺猬因子（Hedgehog）部分通过阻止全长的间断翅脉（Ci-155）转录激活因子被蛋白水解为Ci-75阻遏物形式，来调节靶细胞中的基因表达。Ci-155的蛋白水解依赖于蛋白激酶A（PKA）在三个位点的磷酸化作用。我们发现，这些磷酸丝氨酸会引发相邻的糖原合酶激酶3（GSK3）和酪蛋白激酶I（CK1）位点的进一步磷酸化。改变GSK3或CK1位点可防止Ci-155的蛋白水解，并在没有刺猬因子的情况下激活Ci。如果细胞缺乏先前与无翅信号传导有关的果蝇GSK3（蓬乱蛋白）的活性，Ci-155的蛋白水解也会受到抑制。相反，通过过表达PKA和果蝇CK1（生物钟节律调节因子双倍时间蛋白），刺猬因子反应细胞中的Ci-155水平会降低。
