Oligomerization of the Nrdp1 E3 Ubiquitin Ligase Is Necessary for Efficient Autoubiquitination but Not ErbB3 Ubiquitination

Printsev, Ignat; Yen, Lily; Sweeney, Colleen; Carraway, Kermit L.

doi:10.1074/jbc.m113.527036

Cited by 17 publications

(32 citation statements)

References 49 publications

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“…Immunoprecipitation with an anti‐FLAG antibody revealed that GFP‐Nrdp1 associates with 3× FLAG‐Nrdp1 (Fig. 4A), which is consistent with previous report 19.…”

Section: Resultssupporting

confidence: 92%

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Nrdp1S, short variant of Nrdp1, inhibits human glioma progression by increasing Nrdp1‐mediated ErbB3 ubiquitination and degradation

Wang

Bao

et al. 2015

J Cellular Molecular Medi

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The ubiquitin ligase neuregulin receptor degradation protein 1 (Nrdp1) is involved in the induction of apoptosis and suppression of tumour formation. We previously showed that it was expressed at lower levels in human glioma tissues compared with normal brain tissues. However, the mechanism underlying this is unclear. Here, we reported that a novel short variant (Nrdp1S), lacking 71 amino acids at the N‐terminal, was expressed in normal human brain tissue, but absent from glioma tissues. Similar to Nrdp1, Nrdp1S could be degraded by the proteasomal pathway, but exhibited an even longer half‐life than Nrdp1. Nrdp1S was also shown to form a heterodimer with Nrdp1, which increased its stability, thereby augmenting the Nrdp1‐mediated ubiquitination and degradation of ErbB3. EdU incorporation, MTT assay and in vitro colony formation demonstrated that Nrdp1S significantly inhibited the cell tumourigenicity. These results together suggest that Nrdp1S is a tumour suppressor that which potentiates the Nrdp1‐mediated ubiquitination and degradation of ErbB3. An Nrdp1S deficiency may also be an important factor in the loss of Nrdp1.

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“…Immunoprecipitation with an anti‐FLAG antibody revealed that GFP‐Nrdp1 associates with 3× FLAG‐Nrdp1 (Fig. 4A), which is consistent with previous report 19.…”

Section: Resultssupporting

confidence: 92%

“…Nrdp1 auto‐ubiquitination was also shown to be dependent on the formation of Nrdp1–Nrdp1 homodimers involving the coiled‐coil domains of the proteins 19. It is also showed that the auto‐ubiquitination of Nrdp1 dependents on the formation of Nrdp1*Nrdp1 homodimer by their coiled‐coil domain.…”

Section: Resultsmentioning

confidence: 91%

Nrdp1S, short variant of Nrdp1, inhibits human glioma progression by increasing Nrdp1‐mediated ErbB3 ubiquitination and degradation

Wang

Bao

et al. 2015

J Cellular Molecular Medi

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“…By modeling its CCs, we predicted a trimeric state of RNF41. This is in line with cross-linking and size exclusion chromatography data indicating that RNF41 can self-assemble into a trimeric complex via its CC domain [39]. Similarly, the CC domains of VPS52 were predicted to form trimers (Figs 2E and 3B).…”

Section: Discussionsupporting

confidence: 85%

“…VPS52 co-expression impeded the interaction between Flag-tagged and E-tagged RNF41 in AlphaScreen, whereas co-expression of the VPS52ΔCC mutant partially restored this interaction (Fig 3E). As RNF41 homotrimers are prone to auto-ubiquitination and degradation, disruption of RNF41 homotrimers lead to a more stabilized RNF41 expression [39]. We observed this in S2B Fig, where VPS52 co-expression increases RNF41 monomer expression compared to mock- or VPS52ΔCC- transfected cells.…”

Section: Resultssupporting

confidence: 56%

RNF41 interacts with the VPS52 subunit of the GARP and EARP complexes

et al. 2017

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RNF41 (Ring Finger Protein 41) is an E3 ubiquitin ligase involved in the intracellular sorting and function of a diverse set of substrates. Next to BRUCE and Parkin, RNF41 can directly ubiquitinate ErbB3, IL-3, EPO and RARα receptors or downstream signaling molecules such as Myd88, TBK1 and USP8. In this way it can regulate receptor signaling and routing. To further elucidate the molecular mechanism behind the role of RNF41 in intracellular transport we performed an Array MAPPIT (Mammalian Protein-Protein Interaction Trap) screen using an extensive set of proteins derived from the human ORFeome collection. This paper describes the identification of VPS52, a subunit of the GARP (Golgi-Associated Retrograde Protein) and the EARP (Endosome-Associated Recycling Protein) complexes, as a novel interaction partner of RNF41. Through interaction via their coiled coil domains, RNF41 ubiquitinates and relocates VPS52 away from VPS53, a common subunit of the GARP and EARP complexes, towards RNF41 bodies.

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“…Nrdp1 is a RING-type E3 ubiquitin ligase that was discovered in a yeast 2-hybrid screen, pulled out by the intracellular domain of ErbB3 (Diamonti et al 2002), and provides an essential avenue for steady-state maintenance of ErbB3 protein levels (Yen et al 2006; Printsev et al 2014). Nrdp1 co-localizes and physically associates with newly synthesized ErbB3 at the ER, affecting the ubiquitination and degradation of the nascent receptor.…”

Section: Plasma Membrane Resident Substratesmentioning

confidence: 99%

Membrane Protein Quantity Control at the Endoplasmic Reticulum

2016

Self Cite

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The canonical function of the endoplasmic reticulum-associated degradation (ERAD) system is to enforce quality control among membrane-associated proteins by targeting misfolded secreted, intra-organellar, and intramembrane proteins for degradation. However, increasing evidence suggests that ERAD additionally functions in maintaining appropriate levels of a subset of membrane-associated proteins. In this ‘quantity control’ capacity, ERAD responds to environmental cues to regulate the proteasomal degradation of specific ERAD substrates according to cellular need. In this review, we discuss in detail seven proteins that are targeted by the ERAD quantity control system. Not surprisingly, ERAD-mediated protein degradation is a key regulatory feature of a variety of ER-resident proteins, including HMG-CoA reductase, cytochrome P450 3A4, IP3 receptor, and type II iodothyronine deiodinase. In addition, the ERAD quantity control system plays roles in maintaining the proper stoichiometry of multi-protein complexes by mediating the degradation of components that are produced in excess of the limiting subunit. Perhaps somewhat unexpectedly, recent evidence suggests that the ERAD quantity control system also contributes to the regulation of plasma membrane-localized signaling receptors, including the ErbB3 receptor tyrosine kinase and the GABA neurotransmitter receptors. For these substrates, a proportion of the newly synthesized yet properly folded receptors are diverted for degradation at the ER, and are unable to traffic to the plasma membrane. Given that receptor abundance or concentration within the plasma membrane plays key roles in determining signaling efficiency, these observations may point to a novel mechanism for modulating receptor-mediated cellular signaling.

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Oligomerization of the Nrdp1 E3 Ubiquitin Ligase Is Necessary for Efficient Autoubiquitination but Not ErbB3 Ubiquitination

Cited by 17 publications

References 49 publications

Nrdp1S, short variant of Nrdp1, inhibits human glioma progression by increasing Nrdp1‐mediated ErbB3 ubiquitination and degradation

Nrdp1S, short variant of Nrdp1, inhibits human glioma progression by increasing Nrdp1‐mediated ErbB3 ubiquitination and degradation

RNF41 interacts with the VPS52 subunit of the GARP and EARP complexes

Membrane Protein Quantity Control at the Endoplasmic Reticulum

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