Wang G, Amanai K, Wang B, Jiang J
Center for Developmental Biology and Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9133, USA.
Genes Dev. 2000 Nov 15;14(22):2893-905. doi: 10.1101/gad.843900.
The Hedgehog (Hh) family of secreted proteins controls many aspects of growth and patterning in animal development. In Drosophila, Hh acts by preventing the formation of a truncated repressor form of Cubitus interruptus (Ci) and stimulating the transcriptional activity of full-length Ci. Here, we provide evidence that Costal2 (Cos2) and Suppressor of Fused [Su(fu)] inhibit Ci by tethering it in the cytoplasm, whereas Hh induces nuclear translocaltion of Ci through Fused (Fu). We have identified a 125 amino acid domain in the C-terminal part of Ci that mediates response to Cos2 inhibition. We show that Cos2 binds Ci, prevents its nuclear import, and inhibits its activity via this domain. We also provide evidence that Su(fu) regulates Ci through two distinct mechanisms: (1) Su(fu) blocks Ci nuclear import through the N-terminal region of Ci, and (2) it inhibits the activity of Ci through a mechanism independent of Ci nuclear translocation. Finally, we show that Cos2 is required for transducing high levels of Hh signaling activity, and it does so by alleviating the blockage of Ci activity imposed by Su(fu).
分泌蛋白的刺猬（Hh）家族控制着动物发育中生长和模式形成的许多方面。在果蝇中，Hh通过阻止截短的Ci抑制形式的形成并刺激全长Ci的转录活性来发挥作用。在这里，我们提供证据表明，Costal2（Cos2）和Fused抑制因子[Su（fu）]通过将Ci束缚在细胞质中来抑制Ci，而Hh通过Fused（Fu）诱导Ci的核转位。我们在Ci的C末端部分鉴定出一个125个氨基酸的结构域，该结构域介导对Cos2抑制的反应。我们表明，Cos2结合Ci，阻止其核输入，并通过该结构域抑制其活性。我们还提供证据表明，Su（fu）通过两种不同的机制调节Ci：（1）Su（fu）通过Ci的N末端区域阻止Ci核输入，（2）它通过独立于Ci核转位的机制抑制Ci的活性。最后，我们表明Cos2是转导高水平Hh信号活性所必需的，并且它通过减轻Su（fu）对Ci活性的阻断来做到这一点。
