Nedd4 and Nedd4–2: Closely related ubiquitin-protein ligases with distinct physiological functions

Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
Cell death and differentiation (Impact Factor: 8.18). 07/2009; 17(1):68-77. DOI: 10.1038/cdd.2009.84
Source: PubMed


The Nedd4 (neural precursor cell-expressed developmentally downregulated gene 4) family of ubiquitin ligases (E3s) is characterized by a distinct modular domain architecture, with each member consisting of a C2 domain, 2-4 WW domains, and a HECT-type ligase domain. Of the nine mammalian members of this family, Nedd4 and its close relative, Nedd4-2, represent the ancestral ligases with strong similarity to the yeast, Rsp5. In Saccharomyces cerevisiae Rsp5 has a key role in regulating the trafficking, sorting, and degradation of a large number of proteins in multiple cellular compartments. However, in mammals the Nedd4 family members, including Nedd4 and Nedd4-2, appear to have distinct functions, thereby suggesting that these E3s target specific proteins for ubiquitylation. In this article we focus on the biology and emerging functions of Nedd4 and Nedd4-2, and review recent in vivo studies on these E3s.

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    • "dissecting the mechanism underlying the control of Dvl production is of central importance in understanding CE movements. NEDD4L (neural precursor cell expressed, developmentally downregulated 4-like), a HECT-type E3 ubiquitin ligase, has been shown to be essential for the stability control of multiple cellular proteins including ENαC, activated Smad2/3 and Dvl (Yang and Kumar, 2009; Boase et al., 2011; Kimura et al., 2011; Lee et al., 2009; Rotin and Kumar, 2009; Gao et al., 2009; Ding et al., 2013). In this report we tested the function of NEDD4L in the context of mesodermal convergent extension using Xenopus model organism. "
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    ABSTRACT: During the early vertebrate body plan formation, convergent extension (CE) of dorsal mesoderm and neurectoderm is coordinated by the evolutionarily conserved non-canonical Wnt/PCP signaling. Dishevelled (Dvl), a key mediator of Wnt/PCP signaling, is essential for the medial-lateral polarity formation in the cells undergoing convergent extension movements. NEDD4L, a highly conserved HECT type E3 ligase, has been reported to regulate the stability of multiple substrates including Dvl2. Here we demonstrate that NEDD4L is required for the cellular polarity formation and convergent extension in the early Xenopus embryos. Depletion of NEDD4L in early Xenopus embryos results in the loss of mediolateral polarity of the convergent-extending mesoderm cells and the shortened body axis, resembling those defects caused by the disruption of non-canonical Wnt signaling. Depletion of xNEDD4L also blocks the elongation of the animal explants in response to endogenous mesoderm inducing signals and partially compromises the expression of Brachyury. Importantly, reducing Dvl2 expression can largely rescue the cellular polarity and convergent extension defects in NEDD4L-depleted embryos and explants. Together with the data that NEDD4L reduces Dvl2 protein expression in the frog embryos, our findings suggest that regulation of Dvl protein levels by NEDD4L is essential for convergent extension during early Xenopus embryogenesis.
    Developmental Biology 05/2014; 392(1). DOI:10.1016/j.ydbio.2014.05.003 · 3.55 Impact Factor
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    • "Nedd4-2 regulates other voltage-gated ion channels, such as potassium (K v s and KCNQs) and choride (ClCs) channels, which modulate electrical excitability in neurons (Bongiorno et al. 2011). Nedd4-2 regulation is not restricted to voltage-gated ion channels, but includes interactions with amino acids, dopamine transporters, glutamate transporters, adaptor proteins, and kinases (Yang and Kumar 2009). "
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    ABSTRACT: Ion channel proteins are regulated by different types of posttranslational modifications. The focus of this review is the regulation of voltage-gated sodium channels (Navs) upon their ubiquitylation. The amiloride-sensitive epithelial sodium channel (ENaC) was the first ion channel shown to be regulated upon ubiquitylation. This modification results from the binding of ubiquitin ligase from the Nedd4 family to a protein-protein interaction domain, known as the PY motif, in the ENaC subunits. Many of the Navs have similar PY motifs, which have been demonstrated to be targets of Nedd4-dependent ubiquitylation, tagging them for internalization from the cell surface. The role of Nedd4-dependent regulation of the Nav membrane density in physiology and disease remains poorly understood. Two recent studies have provided evidence that Nedd4-2 is downregulated in dorsal root ganglion (DRG) neurons in both rat and mouse models of nerve injury-induced neuropathic pain. Using two different mouse models, one with a specific knockout of Nedd4-2 in sensory neurons and another where Nedd4-2 was overexpressed with the use of viral vectors, it was demonstrated that the neuropathy-linked neuronal hyperexcitability was the result of Nav1.7 and Nav1.8 overexpression due to Nedd4-2 downregulation. These studies provided the first in vivo evidence of the role of Nedd4-2-dependent regulation of Nav channels in a disease state. This ubiquitylation pathway may be involved in the development of symptoms and diseases linked to Nav-dependent hyperexcitability, such as pain, cardiac arrhythmias, epilepsy, migraine, and myotonias.
    Handbook of experimental pharmacology 04/2014; 221:231-250. DOI:10.1007/978-3-642-41588-3_11
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    • "Ubiquitination is a key process for the regulation of proteins in the cell and failure of ubiquitin pathways in the brain is linked to neuropathological states such as Parkinson's disease (PD) [1]. The targeting of proteins for ubiquitination relies on enzymes known as E3 ubiquitin ligases and their adaptor proteins; together they identify proteins for the addition of ubiquitin resulting in target protein degradation or alternatively, protein trafficking [2]. Ndfip1 is an adaptor protein for the Nedd4 family of ubiquitin ligases and has been found to be upregulated in neurons after brain injury, including head trauma, stroke and metal toxicity [3]–[6]. "
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    ABSTRACT: Iron misregulation is a central component in the neuropathology of Parkinson's disease. The iron transport protein DMT1 is known to be increased in Parkinson's brains linking functional transport mechanisms with iron accumulation. The regulation of DMT1 is therefore critical to the management of iron uptake in the disease setting. We previously identified post-translational control of DMT1 levels through a ubiquitin-mediated pathway led by Ndfip1, an adaptor for Nedd4 family of E3 ligases. Here we show that loss of Ndfip1 from mouse dopaminergic neurons resulted in misregulation of DMT1 levels and increased susceptibility to iron induced death. We report that in human Parkinson's brains increased iron concentrations in the substantia nigra are associated with upregulated levels of Ndfip1 in dopaminergic neurons containing α-synuclein deposits. Additionally, Ndfip1 was also found to be misexpressed in astrocytes, a cell type normally devoid of this protein. We suggest that in Parkinson's disease, increased iron levels are associated with increased Ndfip1 expression for the regulation of DMT1, including abnormal Ndfip1 activation in non-neuronal cell types such as astrocytes.
    PLoS ONE 01/2014; 9(1):e87119. DOI:10.1371/journal.pone.0087119 · 3.23 Impact Factor
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