EGF receptor-independent action of TGF-α protects Naked2 from AO7-mediated ubiquitylation and proteasomal degradation
EGF receptor-independent action of TGF-α protects Naked2 from AO7-mediated ubiquitylation and proteasomal degradation
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DOI：
10.1073/pnas.0806298105
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发表时间：
2008-09-09
影响因子：
11.1
通讯作者：
Coffey, Robert J.
中科院分区：
文献类型：
--
作者：
Ding, Wei;Li, Cunxi;Coffey, Robert J.
裸家族成员（果蝇裸角质层和哺乳动物Naked 1和Naked 2）已被鉴定为典型Wnt信号传导的诱导型拮抗剂。我们最近报道，Naked 2，而不是Naked 1，与TGF-α的胞质尾相互作用，从而覆盖含有TGF-α的胞吐囊泡，并将这些囊泡定向到极化上皮细胞的基底外侧角。在这里，我们发现Naked 2是一种短寿命的蛋白质，其半衰期为60分钟，由其快速的泛素介导的蛋白酶体降解引起。TGF-α的过表达以EGF受体（EGFR）非依赖性方式稳定Naked 2蛋白; TGF-α和Naked 2的胞质尾之间的物理相互作用对于这种保护是必要和充分的。我们已经鉴定了一种RING指蛋白AO 7/RNF 25作为Naked 2的泛素连接酶，并且我们已经表明TGF-α的过表达减少了AO 7与Naked 2的结合。这些结果鉴定了TGF-α的EGFR非依赖性作用，其中它保护Naked 2免受蛋白酶体降解，从而确保其递送至极化上皮细胞的基底外侧表面。
Naked family members (Drosophila Naked Cuticle and mammalian Naked1 and Naked2) have been identified as inducible antagonists of canonical Wnt signaling. We recently reported that Naked2, but not Naked1, interacts with the cytoplasmic tail of TGF-alpha, thereby coating TGF-alpha-containing exocytic vesicles and directing these vesicles to the basolateral corner of polarized epithelial cells. Here, we show that Naked2 is a short-lived protein with a half-life of 60 min caused by its rapid ubiquitin-mediated proteasomal degradation. Overexpression of TGF-alpha stabilizes Naked2 protein in an EGF receptor (EGFR)-independent manner; a physical interaction between the cytoplasmic tail of TGF-alpha and Naked2 is necessary and sufficient for this protection. We have identified a RING finger protein, AO7/RNF25, as a ubiquitin ligase for Naked2, and we have shown that overexpression of TGF-alpha reduces binding of AO7 to Naked2. These results identify an EGFR-independent action of TGF-alpha, in which it protects Naked2 from proteasomal degradation, thus ensuring its delivery to the basolateral surface of polarized epithelial cells.