Fbx8 makes Arf6 refractory to function via ubiquitination
Fbx8 makes Arf6 refractory to function via ubiquitination
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DOI：
10.1091/mbc.e07-08-0763
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发表时间：
2008-03-01
影响因子：
3.3
通讯作者：
Sabe, Hisataka
中科院分区：
文献类型：
--
作者：
Yano, Hajime;Kobayashi, Itaru;Sabe, Hisataka
小的GTP结合蛋白Arf6调节细胞外周的膜重塑，在包括肿瘤侵袭在内的更高层次的细胞功能中发挥关键作用。在这里，我们证明了Fbx8，一种含有Sec7结构域的F-box蛋白，介导了Arf6的泛素化。这种泛素化似乎与Arf6蛋白酶体的即时降解无关，而Fbx8基因敲除导致了Arf6的过度激活。在一些乳腺肿瘤细胞系中，Fbx8蛋白的表达大量缺失，其中Arf6活性是其侵袭的关键。Fbx8在这些细胞中的强制表达抑制了它们的Arf6活性和侵袭活性，其中Fbx8的F-box和sec7结构域是必需的。结合Fbx8介导的泛素化如何干扰Arf6功能的可能机制，我们认为Fbx8通过非规范泛素化对Arf6活性提供了一种新的抑制控制。我们的结果表明，Fbx8表达异常可能与某些乳腺癌细胞的侵袭性有关。
The small GTP-binding protein Arf6 regulates membrane remodeling at cell peripheries and plays crucial roles in higher orders of cellular functions including tumor invasion. Here we show that Fbx8, an F-box protein bearing the Sec7 domain, mediates ubiquitination of Arf6. This ubiquitination did not appear to be linked to immediate proteasomal degradation of Arf6, whereas Fbx8 knockdown caused hyperactivation of Arf6. Expression of Fbx8 protein was substantially lost in several breast tumor cell lines, in which Arf6 activity is pivotal for their invasion. Forced expression of Fbx8 in these cells suppressed their Arf6 activities and invasive activities, in which the F-box and Sec7 domains of Fbx8 are required. Together with the possible mechanism as to how Fbx8-mediated ubiquitination interferes with the functions of Arf6, we propose that Fbx8 provides a novel suppressive control of Arf6 activity through noncanonical ubiquitination. Our results indicate that dysfunction of Fbx8 expression may contribute to the invasiveness of some breast cancer cells.