Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
Development. 2011 Jun;138(12):2533-42. doi: 10.1242/dev.063479.
Hedgehog (Hh) signaling activates full-length Ci/Gli family transcription factors and prevents Ci/Gli proteolytic processing to repressor forms. In the absence of Hh, Ci/Gli processing is initiated by direct Pka phosphorylation. Despite those fundamental similarities between Drosophila and mammalian Hh pathways, the differential reliance on cilia and some key signal transduction components had suggested a major divergence in the mechanisms that regulate Ci/Gli protein activities, including the role of the kinesin-family protein Costal 2 (Cos2), which directs Ci processing in Drosophila. Here, we show that Cos2 binds to three regions of Gli1, just as for Ci, and that Cos2 functions to silence mammalian Gli1 in Drosophila in a Hh-regulated manner. Cos2 and the mammalian kinesin Kif7 can also direct Gli3 and Ci processing in fly, underscoring a fundamental conserved role for Cos2 family proteins in Hh signaling. We also show that direct PKA phosphorylation regulates the activity, rather than the proteolysis of Gli in Drosophilia, and we provide evidence for an analogous action of PKA on Ci.
Hedgehog (Hh) 信号通路激活全长 Ci/Gli 家族转录因子，并防止 Ci/Gli 蛋白发生蛋白酶体切割形成抑制形式。在没有 Hh 的情况下，Ci/Gli 的加工是由直接的 Pka 磷酸化启动的。尽管果蝇和哺乳动物 Hh 途径有这些基本的相似之处，但对纤毛和一些关键信号转导成分的不同依赖表明，调节 Ci/Gli 蛋白活性的机制存在重大差异，包括驱动果蝇 Ci 加工的驱动蛋白家族蛋白 Costal 2 (Cos2) 的作用。在这里，我们表明 Cos2 与 Gli1 的三个区域结合，就像 Ci 一样，并且 Cos2 以 Hh 调节的方式在果蝇中沉默哺乳动物 Gli1。Cos2 和哺乳动物的驱动蛋白 Kif7 也可以在苍蝇中指导 Gli3 和 Ci 的加工，强调 Cos2 家族蛋白在 Hh 信号中的基本保守作用。我们还表明，直接的 PKA 磷酸化调节果蝇中 Gli 的活性，而不是蛋白酶体切割，并且我们提供了 PKA 对 Ci 类似作用的证据。
