The Nedd4-like ubiquitin E3 ligases target angiomotin/p130 to ubiquitin-dependent degradation.
The Nedd4-like ubiquitin E3 ligases target angiomotin/p130 to ubiquitin-dependent degradation.
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DOI：
10.1042/bj20111983
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发表时间：
2012-06
期刊：
影响因子：
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通讯作者：
Chenji Wang;Jian An;Pingzhao Zhang;Chen Xu;K. Gao;Di Wu;Dejie Wang;Hongxiu Yu;Jun O. Liu
中科院分区：
文献类型：
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作者：
Chenji Wang;Jian An;Pingzhao Zhang;Chen Xu;K. Gao;Di Wu;Dejie Wang;Hongxiu Yu;Jun O. Liu
AMOT（angiomotin）是一种膜相关蛋白，其在EC（内皮细胞）中表达并控制迁移、TJ（紧密连接）形成、细胞极性和血管生成。最近的研究表明，AMOT和两个AMOT样蛋白，AMOTL 1和AMOTL 2，通过调节共激活因子雅普（Yes相关蛋白）和TAZ（转录共激活因子与PDZ结合基序）的亚细胞定位在Hippo通路中发挥关键作用。然而，目前尚不清楚AMOT如何监管。在本研究中，我们报告，AMOT经历蛋白酶体降解。我们确定了Nedd 4（神经前体细胞表达的发育下调）样泛素E3连接酶的三个成员，Nedd 4，Nedd 4 -2和Itch，作为AMOT长亚型AMOT/p130的泛素E3连接酶。我们证明Nedd 4，Nedd 4 -2和Itch介导AMOT/p130在体内的多聚泛素化。Nedd 4、Nedd 4 -2或Itch的过表达导致AMOT/p130蛋白酶体降解。Nedd 4、Nedd 4 -2和Itch的敲低导致AMOT/p130的稳态水平的积累。我们还发现，AMOT/p130的三个L/P-PXY基序和Nedd 4的WW结构域介导它们的相互作用。此外，Nedd 4样泛素E3连接酶可能与雅普竞争结合AMOT/p130，并随后靶向AMOT/p130进行泛素依赖性降解。总之，这些观察结果揭示了AMOT/p130的一种新的翻译后调节机制。
AMOT (angiomotin) is a membrane-associated protein that is expressed in ECs (endothelial cells) and controls migration, TJ (tight junction) formation, cell polarity and angiogenesis. Recent studies have revealed that AMOT and two AMOT-like proteins, AMOTL1 and AMOTL2, play critical roles in the Hippo pathway by regulating the subcellular localization of the co-activators YAP (Yes-associated protein) and TAZ (transcriptional co-activator with PDZ-binding motif). However, it has been unclear how AMOT is regulated. In the present study, we report that AMOT undergoes proteasomal degradation. We identify three members of Nedd4 (neural-precursor-cell-expressed developmentally down-regulated)-like ubiquitin E3 ligases, Nedd4, Nedd4-2 and Itch, as the ubiquitin E3 ligases for the long isoform of AMOT, AMOT/p130. We demonstrate that Nedd4, Nedd4-2 and Itch mediate poly-ubiquitination of AMOT/p130 in vivo. Overexpression of Nedd4, Nedd4-2 or Itch leads to AMOT/p130 proteasomal degradation. Knockdown of Nedd4, Nedd4-2 and Itch causes an accumulation of steady-state level of AMOT/p130. We also show that three L/P-PXY motifs of AMOT/p130 and the WW domains of Nedd4 mediate their interaction. Furthermore, Nedd4-like ubiquitin E3 ligases might compete with YAP for the binding to AMOT/p130, and subsequently targeting AMOT/p130 for ubiquitin-dependent degradation. Together, these observations reveal a novel post-translational regulatory mechanism of AMOT/p130.