Elsevier

Gene

Volume 557, Issue 2, 25 February 2015, Pages 113-122
Gene

Review
NEDD4: The founding member of a family of ubiquitin-protein ligases

https://doi.org/10.1016/j.gene.2014.12.020Get rights and content

Highlights

  • NEDD4 is the founding member of a family of ubiquitin protein ligases.

  • NEDD4 ubiquitinates several membrane and cytosolic proteins, and regulates key signaling pathways.

  • The best studied targets of NEDD4 include the components of the IGF-1R-mediated growth signaling pathway.

  • NEDD4 deletion in mice leads to multiple developmental defects and embryonic lethality.

Abstract

Ubiquitination plays a crucial role in regulating proteins post-translationally. The focus of this review is on NEDD4, the founding member of the NEDD4 family of ubiquitin ligases that is evolutionarily conserved in eukaryotes. Many potential substrates of NEDD4 have been identified and NEDD4 has been shown to play a critical role in the regulation of a number of membrane receptors, endocytic machinery components and the tumour suppressor PTEN. In this review we will discuss the diverse pathways in which NEDD4 is involved, and the patho-physiological significance of this important ubiquitin ligase.

Introduction

Ubiquitination is a post-translational protein modification that is critical for a number of cellular processes. Ubiquitination involves the covalent attachment of the 8 kDa protein ubiquitin to one or more lysine residues in the substrate protein to signal proteins for degradation, altered localisation, trafficking or function. Substrate proteins can be mono-ubiquitinated, multi-monoubiquitinated or poly-ubiquitinated, with the type of ubiquitination determining the fate of the protein. Ubiquitin itself has seven lysine residues, allowing for different ubiquitin linkage types; for example the well-studied K48-linkage typically targets proteins for proteasomal degradation (Hershko and Ciechanover, 1998) whereas K63 linkages are associated with protein trafficking and lysosomal degradation (Hicke and Dunn, 2003).

Ubiquitin is covalently attached to a protein substrate via an energy dependent three step process, involving an E1 ubiquitin activating enzyme, an E2 ubiquitin conjugating enzyme and an E3 ubiquitin protein ligase. The E3 ubiquitin ligase largely determines the substrate specificity of the system and in mammals there are several hundred ubiquitin protein ligases (Hershko and Ciechanover, 1998). These can be grouped into two main classes; the RING (Really Interesting New Gene) E3s which mediate the direct transfer of ubiquitin to the substrate (Deshaies and Joazeiro, 2009), and the HECT (Homologous to E6-AP C-Terminus) E3s which are involved in the transfer of activated ubiquitin from the E2 to the substrate by forming an intermediate complex with the C-terminus of the E3 (Rotin and Kumar, 2009). This review will focus on the HECT type ubiquitin ligase NEDD4, one of the first HECT E3 ligases discovered, and the founding member of the NEDD4 family of HECT ubiquitin ligases.

Section snippets

History of NEDD4 discovery

The NEDD4 gene was cloned in 1992 as one of a number of murine Nedd (Neural precursor cell expressed developmentally down-regulated) genes differentially expressed in the central nervous system (Kumar et al., 1992). At the time of its cloning, the predicted protein had only one known domain — an N-terminal calcium/lipid-binding domain (C2 domain). The presence of three partial repeats of approximately 40 amino acids containing two conserved tryptophan residues in the middle part of the protein

NEDD4 orthologues and structure

As mentioned above, NEDD4 is a highly evolutionarily conserved protein from yeast to man, and was initially cloned as a highly expressed gene in the early embryonic brain (Kumar et al., 1992, Kumar et al., 1997). There are 94 orthologues of NEDD4 in the NCBI database, all sharing the same modular structure consisting of an N-terminal C2 domain, 3–4 WW domains and a C-terminal catalytic HECT domain for ubiquitin protein ligation (Harvey and Kumar, 1999) (Fig. 1A). The C2 domain is a

NEDD4 binding partners and targets

A number of in vitro binding studies and proteomic approaches have been used to identify potential NEDD4 substrates (see below for a summary and Table 1 for a list of interacting proteins).

Physiological functions of NEDD4

NEDD4 is widely expressed in mammalian tissues. To investigate the physiological functions of NEDD4, a number of studies have focussed on NEDD4−/− mice that lack NEDD4 expression. The first described NEDD4−/− mice were neonatal lethal, with delayed embryonic development and reduced growth and body weight due (Cao et al., 2008). Consistent with this, NEDD4−/− murine embryonic fibroblasts (MEFs) display reduced mitogenic activity (Cao et al., 2008). NEDD4−/− embryos have reduced skeletal muscle

NEDD4 auto-inhibition

NEDD4 activity is in part regulated by auto-inhibition. In the absence of calcium, an auto-inhibitory conformation of NEDD4 is formed by the C2 domain of NEDD4 binding to the HECT domain via intramolecular interactions, thereby inhibiting the enzymatic activity of NEDD4 (Wang et al., 2010). In the presence of calcium, the binding of the C2 domain to the HECT domain is disrupted and the C2 domain recruits NEDD4 to the lipid membrane promoting its ubiquitin ligase activity (Wang et al., 2010).

Conclusions

NEDD4 is the founding member of the NEDD4 family of ubiquitin protein ligases that function in the ubiquitin proteasome system. NEDD4 has many important cellular functions, as indicated by the high degree of evolutionary conservation observed across many species. NEDD4 has roles in regulating viral budding, IGF-1 signalling, in T-cell function and in PTEN signalling, although this is yet to be fully understood as there are currently a number of conflicting models. The role of NEDD4 in cancer

Acknowledgements

The ubiquitin work in our laboratory is supported by the National Health and Medical Research Council (NHMRC) Project Grants 1020755 & 1059393, and a NHMRC Senior Principal Research Fellowship 1002863 to SK.

References (121)

  • N.J. Foot et al.

    Regulation of the divalent metal ion transporter DMT1 and iron homeostasis by a ubiquitin-dependent mechanism involving Ndfips and WWP2

    Blood

    (2008)
  • N.J. Foot et al.

    Ndfip1-deficient mice have impaired DMT1 regulation and iron homeostasis

    Blood

    (2011)
  • A.B. Fotia et al.

    Regulation of neuronal voltage-gated sodium channels by the ubiquitin-protein ligases Nedd4 and Nedd4-2

    J. Biol. Chem.

    (2004)
  • A.B. Fotia et al.

    The ubiquitin-protein ligases Nedd4 and Nedd4-2 show similar ubiquitin-conjugating enzyme specificities

    Int. J. Biochem. Cell Biol.

    (2006)
  • F. Fouladkou et al.

    The ubiquitin ligase Nedd4-1 is required for heart development and is a suppressor of thrombospondin-1

    J. Biol. Chem.

    (2010)
  • H. Girao et al.

    Eps15 interacts with ubiquitinated Cx43 and mediates its internalization

    Exp. Cell Res.

    (2009)
  • H. Guo et al.

    E3 ubiquitin ligase Cbl-b regulates Pten via Nedd4 in T cells independently of its ubiquitin ligase activity

    Cell Rep.

    (2012)
  • K.F. Harvey et al.

    Nedd4-like proteins: an emerging family of ubiquitin-protein ligases implicated in diverse cellular functions

    Trends Cell Biol.

    (1999)
  • K.F. Harvey et al.

    The Nedd4-like protein KIAA0439 is a potential regulator of the epithelial sodium channel

    J. Biol. Chem.

    (2001)
  • M. Ikeda et al.

    The Epstein–Barr virus latent membrane protein 2A PY motif recruits WW domain-containing ubiquitin-protein ligases

    Virology

    (2000)
  • H. Kawabe et al.

    Regulation of Rap2A by the ubiquitin ligase Nedd4-1 controls neurite development

    Neuron

    (2010)
  • S. Kumar et al.

    Identification of a set of genes with developmentally down-regulated expression in the mouse brain

    Biochem. Biophys. Res. Commun.

    (1992)
  • S. Kumar et al.

    cDNA cloning, expression analysis, and mapping of the mouse Nedd4 gene

    Genomics

    (1997)
  • Y.D. Kwak et al.

    Functional interaction of phosphatase and tensin homologue (PTEN) with the E3 ligase NEDD4-1 during neuronal response to zinc

    J. Biol. Chem.

    (2010)
  • Y. Liu et al.

    Abnormal development of the neuromuscular junction in Nedd4-deficient mice

    Dev. Biol.

    (2009)
  • A. Magnifico et al.

    WW domain HECT E3s target Cbl RING finger E3s for proteasomal degradation

    J. Biol. Chem.

    (2003)
  • O.A. Malakhova et al.

    ISG15 inhibits Nedd4 ubiquitin E3 activity and enhances the innate antiviral response

    J. Biol. Chem.

    (2008)
  • A. Morrione et al.

    mGrb10 interacts with Nedd4

    J. Biol. Chem.

    (1999)
  • J. Murdaca et al.

    Grb10 prevents Nedd4-mediated vascular endothelial growth factor receptor-2 degradation

    J. Biol. Chem.

    (2004)
  • U. Putz et al.

    Nedd4 family-interacting protein 1 (Ndfip1) is required for the exosomal secretion of Nedd4 family proteins

    J. Biol. Chem.

    (2008)
  • M. Rost et al.

    gamma2-Adaptin, a ubiquitin-interacting adaptor, is a substrate to coupled ubiquitination by the ubiquitin ligase Nedd4 and functions in the endosomal pathway

    J. Biol. Chem.

    (2008)
  • J.S. Rougier et al.

    Neuronal precursor cell-expressed developmentally down-regulated 4-1 (NEDD4-1) controls the sorting of newly synthesized Ca(V)1.2 calcium channels

    J. Biol. Chem.

    (2011)
  • T. Sakata et al.

    Drosophila Nedd4 regulates endocytosis of notch and suppresses its ligand-independent activation

    Curr. Biol.

    (2004)
  • M. Scheffner et al.

    Mammalian HECT ubiquitin-protein ligases: biological and pathophysiological aspects

    Biochim. Biophys. Acta

    (2014)
  • M. Scheffner et al.

    The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53

    Cell

    (1993)
  • M. Screen et al.

    Abnormal splicing of NEDD4 in myotonic dystrophy type 2: possible link to statin adverse reactions

    Am. J. Pathol.

    (2014)
  • C. Segura-Morales et al.

    Tsg101 and Alix interact with murine leukemia virus Gag and cooperate with Nedd4 ubiquitin ligases during budding

    J. Biol. Chem.

    (2005)
  • T. Anan et al.

    Human ubiquitin-protein ligase Nedd4: expression, subcellular localization and selective interaction with ubiquitin-conjugating enzymes

    Genes Cells

    (1998)
  • I. Aronchik et al.

    The anti-proliferative response of indole-3-carbinol in human melanoma cells is triggered by an interaction with NEDD4–1 and disruption of wild-type PTEN degradation

    Mol. Cancer Res.

    (2014)
  • N.A. Boase et al.

    Respiratory distress and perinatal lethality in Nedd4-2-deficient mice

    Nat. Commun.

    (2011)
  • X.R. Cao et al.

    Nedd4 controls animal growth by regulating IGF-1 signaling

    Sci. Signal.

    (2008)
  • C. Chen et al.

    The Nedd4-like family of E3 ubiquitin ligases and cancer

    Cancer Metastasis Rev.

    (2007)
  • B. Dai et al.

    FoxM1B regulates NEDD4-1 expression, leading to cellular transformation and full malignant phenotype in immortalized human astrocytes

    Cancer Res.

    (2010)
  • H.E. Dalton et al.

    Drosophila Ndfip is a novel regulator of Notch signaling

    Cell Death Differ.

    (2011)
  • R.J. Deshaies et al.

    RING domain E3 ubiquitin ligases

    Annu. Rev. Biochem.

    (2009)
  • A. Dinudom et al.

    Nedd4 mediates control of an epithelial Na + channel in salivary duct cells by cytosolic Na +

    Proc. Natl. Acad. Sci. U. S. A.

    (1998)
  • R. Dunn et al.

    The C2 domain of the Rsp5 ubiquitin ligase binds membrane phosphoinositides and directs ubiquitination of endosomal cargo

    J. Cell Biol.

    (2004)
  • D. Fang et al.

    Dysregulation of T lymphocyte function in itchy mice: a role for Itch in TH2 differentiation

    Nat. Immunol.

    (2002)
  • D.F. Fang et al.

    NEDD4 ubiquitinates TRAF3 to promote CD40-mediated AKT activation

    Nat. Commun.

    (2014)
  • J. Fombonne et al.

    Patched dependence receptor triggers apoptosis through ubiquitination of caspase-9

    Proc. Natl. Acad. Sci. U. S. A.

    (2012)
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