E3 ubiquitin-protein ligase NEDD4-like

Definition:

E3 ubiquitin-protein ligase that mediates the polyubiquitination of lysine and cysteine residues on target proteins and is thereby implicated in the regulation of various signaling pathways including autophagy, innate immunity or DNA repair. Inhibits TGF-beta signaling by triggering SMAD2 and TGFBR1 ubiquitination and proteasome-dependent degradation. Downregulates autophagy and cell growth by ubiquitinating and reducing cellular ULK1 or ASCT2 levels. Promotes ubiquitination and internalization of various plasma membrane channels such as ENaC, SCN2A/Nav1.2, SCN3A/Nav1.3, SCN5A/Nav1.5, SCN9A/Nav1.7, SCN10A/Nav1.8, KCNA3/Kv1.3, KCNH2, EAAT1, KCNQ2/Kv7.2, KCNQ3/Kv7.3 or CLC5. Promotes ubiquitination and degradation of SGK1 and TNK2. Ubiquitinates BRAT1 and this ubiquitination is enhanced in the presence of NDFIP1. Plays a role in dendrite formation by melanocytes. Involved in the regulation of TOR signaling. Ubiquitinates and regulates protein levels of NTRK1 once this one is activated by NGF. Plays a role in antiviral innate immunity by catalyzing 'Lys-29'-linked cysteine ubiquitination of TRAF3, resulting in enhanced 'Lys-48' and 'Lys-63'-linked ubiquitination of TRAF3.

References:

[1]. Begoña Anta, et al. Ubiquitin-specific Protease 36 (USP36) Controls Neuronal Precursor Cell-expressed Developmentally Down-regulated 4-2 (Nedd4-2) Actions over the Neurotrophin Receptor TrkA and Potassium Voltage-gated Channels 7.2/3 (Kv7.2/3). J Biol Chem. 2016 Sep 2;291(36):19132-45. [Content Brief]

[2]. Go Kuratomi, et al. NEDD4-2 (neural precursor cell expressed, developmentally down-regulated 4-2) negatively regulates TGF-beta (transforming growth factor-beta) signalling by inducing ubiquitin-mediated degradation of Smad2 and TGF-beta type I receptor. Biochem J. 2005 Mar 15;386(Pt 3):461-70. [Content Brief]

[3]. Francesca Nazio, et al. ULK1 ubiquitylation is regulated by phosphorylation on its carboxy terminus. Cell Cycle. 2017 Oct 2;16(19):1744-1747. [Content Brief]

[4]. Jae Cheal Yoo, et al. SYT14L, especially its C2 domain, is involved in regulating melanocyte differentiation. J Dermatol Sci. 2013 Dec;72(3):246-51. [Content Brief]

[5]. Dong-Eun Lee, et al. NEDD4L downregulates autophagy and cell growth by modulating ULK1 and a glutamine transporter. Cell Death Dis. 2020 Jan 20;11(1):38. [Content Brief]

[6]. Wing Chan, et al. Down-regulation of active ACK1 is mediated by association with the E3 ubiquitin ligase Nedd4-2. J Biol Chem. 2009 Mar 20;284(12):8185-94. [Content Brief]

[7]. Miguel X van Bemmelen, et al. Cardiac voltage-gated sodium channel Nav1.5 is regulated by Nedd4-2 mediated ubiquitination. Circ Res. 2004 Aug 6;95(3):284-91. [Content Brief]

[8]. Peng Gao, et al. E3 ligase Nedd4l promotes antiviral innate immunity by catalyzing K29-linked cysteine ubiquitination of TRAF3. Nat Commun. 2021 Feb 19;12(1):1194. [Content Brief]

[9]. Ruifeng Zhou, et al. Nedd4-2 phosphorylation induces serum and glucocorticoid-regulated kinase (SGK) ubiquitination and degradation. J Biol Chem. 2005 Feb 11;280(6):4518-23. [Content Brief]

[10]. Yudi Kang, et al. Regulation of the human ether-a-go-go-related gene (hERG) potassium channel by Nedd4 family interacting proteins (Ndfips). Biochem J. 2015 Nov 15;472(1):71-82. [Content Brief]

[11]. Hari B Kamadurai, et al. Insights into ubiquitin transfer cascades from a structure of a UbcH5B approximately ubiquitin-HECT(NEDD4L) complex. Mol Cell. 2009 Dec 25;36(6):1095-102. [Content Brief]

[12]. Loïc Broix, et al. Mutations in the HECT domain of NEDD4L lead to AKT-mTOR pathway deregulation and cause periventricular nodular heterotopia. Nat Genet. 2016 Nov;48(11):1349-1358. [Content Brief]

[13]. Deanne H Hryciw, et al. Nedd4-2 functionally interacts with ClC-5: involvement in constitutive albumin endocytosis in proximal tubule cells. J Biol Chem. 2004 Dec 31;279(53):54996-5007. [Content Brief]

[14]. G Henke, et al. Regulation of the voltage gated K+ channel Kv1.3 by the ubiquitin ligase Nedd4-2 and the serum and glucocorticoid inducible kinase SGK1. J Cell Physiol. 2004 May;199(2):194-9. [Content Brief]

[15]. Christoph Boehmer, et al. Regulation of the glutamate transporter EAAT1 by the ubiquitin ligase Nedd4-2 and the serum and glucocorticoid-inducible kinase isoforms SGK1/3 and protein kinase B. J Neurochem. 2003 Sep;86(5):1181-8. [Content Brief]

[16]. Ley-Hian Low, et al. Nedd4 family interacting protein 1 (Ndfip1) is required for ubiquitination and nuclear trafficking of BRCA1-associated ATM activator 1 (BRAT1) during the DNA damage response. J Biol Chem. 2015 Mar 13;290(11):7141-50. [Content Brief]

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