NEDL2 regulates enteric nervous system and kidney development in its Nedd8 ligase activity-dependent manner.
NEDL2 regulates enteric nervous system and kidney development in its Nedd8 ligase activity-dependent manner.
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DOI：
10.18632/oncotarget.8951
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发表时间：
2016-05-24
期刊：
影响因子：
--
通讯作者：
Zhang L
中科院分区：
文献类型：
--
作者：
Qiu X;Wei R;Li Y;Zhu Q;Xiong C;Chen Y;Zhang Y;Lu K;He F;Zhang L
GDNF（Glial cell line-derived neurotrophic factor，胶质细胞源性神经营养因子）/Ret/Akt信号通路对肠神经系统（enteric nervous system，ENS）和肾脏的发育至关重要。我们以前表明，HECT型E3连接酶NEDL 2（Nedd 4样连接酶2）是通过激活GDNF/Ret/Akt来促进ENS发育所必需的。然而，其潜在机制仍不清楚。在这里，我们表明，除了ENS，NEDL 2也是肾脏发育的关键，因为约1/3的NEDL 2缺陷小鼠显示出生后单侧或双侧肾积水。Nedl 1和Nedl 2双基因敲除小鼠在出生后2周内死亡，表型与Nedl 2单基因敲除小鼠相似。令人惊讶的是，其密切成员NEDL 1与ENS和肾功能相关，原因是在早期发育期间这些系统中缺乏NEDL 1表达。此外，生化分析表明，NEDL 2似乎像支架蛋白一样募集SHC，Grb 2，PI 3 K（p110和p85），PDK 1和Akt一起促进信号转导。有趣的是，我们发现NEDL 2具有内在的Nedd 8连接酶活性，半胱氨酸1341作为核心位点。NEDL 2上调GDNF刺激的Akt活性依赖于其Nedd 8连接酶活性，而不是其泛素连接酶活性。这些发现表明，NEDL 2而不是NEDL 1是ENS和肾脏发育所需的独特Nedd 8连接酶依赖性方式。
The GDNF (Glial cell line-derived neurotrophic factor)/Ret/Akt signaling pathway is essential to the development of ENS (enteric nervous system) as well as kidney. We previously showed that the HECT-type E3 ligase NEDL2 (Nedd4-like ligase 2) is required for the ENS development by activating GDNF/Ret/Akt. However, the underlying mechanism remains unknown. Here we show that in addition to ENS, NEDL2 is also pivotal for kidney development since about 1/3 of Nedl2-deficient mice displayed postnatal unilateral or bilateral kidney hydronephrosis. Double knockout of Nedl1 and Nedl2 in mice leads to postnatal lethal within 2 weeks and the phenotypes resemble those of Nedl2 single knockout mice. Surprisingly, its close member NEDL1 is dispensable for ENS and kidney function and the reason is lack of NEDL1 expression in these systems during early development. Furthermore, biochemical analysis indicated that NEDL2 appears to act like a scaffold protein to recruit SHC, Grb2, PI3K (p110 and p85), PDK1 and Akt together to promote the signaling transduction. Intriguingly, we found that NEDL2 harbours intrinsic Nedd8 ligase activity with cysteine 1341 as the core site. NEDL2 upregulates GDNF-stimulated Akt activity dependent of its Nedd8 ligase activity but not its ubiquitin ligase activity. These findings demonstrate that NEDL2 but not NEDL1 is required for ENS and kidney development in a unique Nedd8 ligase-dependent manner.
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影响因子：
64.8
作者：
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DOI：
10.1126/science.1175065
发表时间：
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期刊：
Science (New York, N.Y.)
影响因子：
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