Cdc37 Regulates Ryk Signaling by Stabilizing the Cleaved Ryk Intracellular Domain
Cdc37 Regulates Ryk Signaling by Stabilizing the Cleaved Ryk Intracellular Domain
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DOI：
10.1074/jbc.m900207200
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发表时间：
2009-05-08
影响因子：
4.8
通讯作者：
Lu, Wange
中科院分区：
文献类型：
--
作者：
Lyu, Jungmook;Wesselschmidt, Robin L.;Lu, Wange
Ryk是一种Wnt受体，在神经发生、神经突生长和轴突引导中起重要作用。我们已经报道了Ryk受体被γ -分泌酶切割，其胞内结构域（ICD）在Wnt刺激下易位到细胞核。Ryk及其ICD的分裂对Ryk在神经发生中的功能至关重要。然而，Ryk ICD是如何稳定并转运到细胞核中的问题仍然没有答案。在这里，我们发现Ryk ICD经历泛素化和蛋白酶体降解。我们已经鉴定出分子伴侣Hsp90复合体的一个亚基Cdc37是一种抑制Ryk ICD蛋白酶体降解的Ryk ICD相互作用蛋白。Cdc37过表达增加Ryk ICD水平并促进其核定位，而Cdc37敲低则降低Ryk ICD的稳定性。此外，我们发现Cdc37-Ryk ICD复合物在胚胎干细胞的神经分化过程中被破坏，导致Ryk ICD降解。这些结果表明，Cdc37在调节Ryk ICD稳定性和Ryk介导的信号转导中起重要作用。
Ryk is a Wnt receptor that plays an important role in neurogenesis, neurite outgrowth, and axon guidance. We have reported that the Ryk receptor is cleaved by gamma-secretase and that its intracellular domain (ICD) translocates to the nucleus upon Wnt stimulation. Cleavage of Ryk and its ICD is important for the function of Ryk in neurogenesis. However, the question of how the Ryk ICD is stabilized and translocated into the nucleus remains unanswered. Here, we show that the Ryk ICD undergoes ubiquitination and proteasomal degradation. We have identified Cdc37, a subunit of the molecular chaperone Hsp90 complex, as a Ryk ICD-interacting protein that inhibits proteasomal degradation of the Ryk ICD. Overexpression of Cdc37 increases Ryk ICD levels and promotes its nuclear localization, whereas Cdc37 knockdown reduces Ryk ICD stability. Furthermore, we have discovered that the Cdc37-Ryk ICD complex is disrupted during neural differentiation of embryonic stem cells, resulting in Ryk ICD degradation. These results suggest that Cdc37 plays an essential role in regulating Ryk ICD stability and therefore in Ryk-mediated signal transduction.