Fused kinase is stabilized by Cdc37/Hsp90 and enhances Gli protein levels
Fused kinase is stabilized by Cdc37/Hsp90 and enhances Gli protein levels
复制标题
DOI：
10.1016/j.bbrc.2006.10.036
复制
发表时间：
2006-12-08
影响因子：
3.1
通讯作者：
Miki, Hiroaki
中科院分区：
文献类型：
--
作者：
Kise, Yoshiaki;Takenaka, Kei;Miki, Hiroaki
丝氨酸/苏氨酸激酶融合蛋白（Fu）是果蝇Hedgehog（Hh）信号转导的重要组成部分，但其生物化学功能尚不清楚。在这里，我们研究了蛋白质共沉淀与哺乳动物Fu和确定激酶特异性伴侣复合物，Cdc 37/Hsp 90，作为一种新的结合伙伴的Fu。格尔德霉素（GA）抑制热休克蛋白90的功能，通过泛素-蛋白酶体途径诱导Fu的快速降解。我们接下来表明，Fu与转录因子Gli 1和Gli 2的共表达显著增加了它们的蛋白水平和荧光素酶报告活性，这被GA阻断。这些增加可归因于Fu介导的Gli稳定，因为Fu的共表达延长了Gli 1的半衰期并减少了Gli 1的多聚泛素化。最后，我们表明，GA抑制PC 3，Hh信号激活的前列腺癌细胞系的增殖。异位Gli 1的表达部分挽救了这种生长抑制，表明Fu可能有助于增强癌细胞中的Hh信号传导活性。(c)2006爱思唯尔公司All rights reserved.
Serine/threonine kinase Fused (Fu) is an essential component of Hedgehog (Hh) signaling in Drosophila, but the biochemical functions of Fu remain unclear. Here, we have investigated proteins co-precipitated with mammalian Fu and identified a kinase-specific chaperone complex, Cdc37/Hsp90, as a novel-binding partner of Fu. Inhibition of Hsp90 function by geldanamycin (GA) induces rapid degradation of Fu through a ubiquitin-proteasome pathway. We next show that co-expression of Fu with transcription factors Gli1 and Gli2 significantly increases their protein levels and luciferase reporter activities, which are blocked by GA. These increases can be ascribed to Fu-mediated stabilization of Gli because co-expression of Fu prolongs half-life of Gli1 and reduces polyubiquitination of Gli1. Finally, we show that GA inhibits proliferation of PC3, a Hh signaling-activated prostate cancer cell line. This growth inhibition is partially rescued by expression of ectopic Gli1, suggesting that Fu may contribute to enhance Hh signaling activity in cancer cells. (c) 2006 Elsevier Inc. All rights reserved.