NEDL2 regulates enteric nervous system and kidney development in its Nedd8 ligase activity-dependent manner
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Xiao Qiu1,2, Rongfei Wei1,2, Yang Li4, Qiong Zhu2,3, Cong Xiong1, Yuhan Chen2, Yuan Zhang2, Kefeng Lu2, Fuchu He1,2, Lingqiang Zhang2,3
1School of Life Sciences, Tsinghua University, Beijing 100084, China
2State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China
3Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China
4Department of Experimental Pathology, Beijing Institute of Radiation Medicine, Beijing 100850, China
Lingqiang Zhang, email: [email protected]
Fuchu He, email: [email protected]
Keywords: kidney development, GDNF/Ret/Akt pathway, scaffold protein, ubiquitin ligase, Nedd8 ligase
Received: November 25, 2015 Accepted: April 11, 2016 Published: April 23, 2016
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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