Fused-Costal2 protein complex regulates Hedgehog-induced Smo phosphorylation and cell-surface accumulation
Fused-Costal2 protein complex regulates Hedgehog-induced Smo phosphorylation and cell-surface accumulation
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DOI：
10.1101/gad.1557407
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发表时间：
2007-08-01
影响因子：
10.5
通讯作者：
Jia, Jianhang
中科院分区：
文献类型：
--
作者：
Liu, Yajuan;Cao, Xuesong;Jia, Jianhang
七跨膜蛋白Smoothened（Smo）在Hedgehog（Hh）通路中作为信号转导子，介导许多关键的发育过程。在果蝇中，Hh诱导的磷酸化促进Smo细胞表面积累和信号传导活性;然而，控制Smo磷酸化和细胞表面积累的机制仍然未知。含有Fused（Fu）和Costal 2（Cos 2）的细胞内信号传导复合物被认为是Smo下游的Hh信号传导。在这里，我们确定了一种新的反馈机制，通过Fu-Cos 2复合物调节Smo。我们发现，Hh诱导的Smo积累在fu突变体克隆或表达显性负性形式的Fu中受到抑制，并且这种抑制通过去除Cos 2而减轻。相反，过表达Cos 2会阻止Smo积累，而共表达Fu会逆转这一情况。Cos 2通过其C-末端Smo相互作用结构域阻断Smo积累，Fu通过在Ser 572磷酸化Cos 2拮抗Cos 2。此外，我们发现Ser 572磷酸化减弱了Cos 2-Smo相互作用并促进了Cos 2不稳定性。最后，我们提供的证据表明Fu和Cos 2通过调节Smo磷酸化来控制Smo细胞表面积累。我们的数据表明，Cos 2-Smo相互作用阻断Hh诱导的Smo磷酸化，Fu通过拮抗Cos 2促进Smo磷酸化。
The seven-transmembrane protein Smoothened (Smo) acts as a signal transducer in the Hedgehog (Hh) pathway that mediates many key developmental processes. In Drosophila, Hh-induced phosphorylation promotes Smo cell-surface accumulation and signaling activity; however, the mechanisms controlling Smo phosphorylation and cell-surface accumulation are still unknown. The intracellular signaling complex containing Fused (Fu) and Costal2 (Cos2) is thought to transduce the Hh signal downstream from Smo. Here, we identify a novel feedback mechanism that regulates Smo through the Fu-Cos2 complex. We found that Hh-induced Smo accumulation is inhibited in fu mutant clones or by expressing a dominant-negative form of Fu, and such inhibition is alleviated by removal of Cos2. Conversely, overexpressing Cos2 blocks Smo accumulation, which is reversed by coexpressing Fu. Cos2 blocks Smo accumulation through its C-terminal Smo-interacting domain, and Fu antagonizes Cos2 by phosphorylating Cos2 at Ser572. Furthermore, we found that Ser572 phosphorylation attenuates the Cos2-Smo interaction and promotes Cos2 instability. Finally, we provided evidence that Fu and Cos2 control Smo cell-surface accumulation by regulating Smo phosphorylation. Our data suggest that Cos2-Smo interaction blocks Hh-induced Smo phosphorylation, and that Fu promotes Smo phosphorylation by antagonizing Cos2.