Structural and Biochemical Basis for Ubiquitin Ligase Recruitment by Arrestin-related Domain-containing Protein-3 (ARRDC3)

Qi, Shiqian; O’Hayre, Morgan; Gutkind, J. Silvio; Hurley, James H.

doi:10.1074/jbc.m113.527473

Cited by 66 publications

(87 citation statements)

References 37 publications

(33 reference statements)

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“…2D). The observation that ARRDC3 is ubiquitinated was not surprising because it interacts with the HECT-domain E3 ubiquitin ligases via its PPXY motifs (15,18,19). Interestingly, although ARRDC3 interacts with the ESCRT-0 complex on EEA1-positive early endosomes (19), ARRDC3-AASA/AALA does not.…”

Section: Discussionmentioning

confidence: 99%

“…PPXY motifs often interact with WW-domains, and ARRDCs have been shown to interact with the WW-domain of various HECT-domain E3 ubiquitin ligases (15)(16)(17). Indeed, the first PPXY motif of ARRDC3 has been shown to interact with the third WW domain of Nedd4 with high affinity in vitro (18). Mutations of either the PPXY motifs of ARRDC3 or WW domains of Nedd4 inhibit the interaction between these two proteins in cells (15,18).…”

Section: G Protein-coupled Receptor (Gpcr)mentioning

confidence: 99%

“…Indeed, the first PPXY motif of ARRDC3 has been shown to interact with the third WW domain of Nedd4 with high affinity in vitro (18). Mutations of either the PPXY motifs of ARRDC3 or WW domains of Nedd4 inhibit the interaction between these two proteins in cells (15,18).…”

Section: G Protein-coupled Receptor (Gpcr)mentioning

confidence: 99%

“…Because ARRDC3 interacts with Nedd4 family ubiquitin ligases via its PPXY motifs (15,18,19), we tested whether ARRDC3 was ubiquitinated and, if so, whether the ubiquitination status of ARRDC3 played a role in its localization. We monitored the ubiquitination status of transfected GFP-tagged wild type and mutant ARRDC3 by immunoprecipitating ARRDC3 and blotting for endogenous ubiquitin.…”

Section: Arrdc3 Is Localized On Eea1-positive Early Endosomes Andmentioning

confidence: 99%

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The α-Arrestin ARRDC3 Regulates the Endosomal Residence Time and Intracellular Signaling of the β2-Adrenergic Receptor

Tian

Irannejad

Bowman

et al. 2016

Journal of Biological Chemistry

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Arrestin domain-containing protein 3 (ARRDC3) is a member of the mammalian ␣-arrestin family, which is predicted to share similar tertiary structure with visual-/␤-arrestins and also contains C-terminal PPXY motifs that mediate interaction with E3 ubiquitin ligases. Recently, ARRDC3 has been proposed to play a role in regulating the trafficking of G protein-coupled receptors, although mechanistic insight into this process is lacking. Here, we focused on characterizing the role of ARRDC3 in regulating the trafficking of the ␤ 2 -adrenergic receptor (␤ 2 AR). We find that ARRDC3 primarily localizes to EEA1-positive early endosomes and directly interacts with the ␤ 2 AR in a ligand-independent manner. Although ARRDC3 has no effect on ␤ 2 AR endocytosis or degradation, it negatively regulates ␤ 2 AR entry into SNX27-occupied endosomal tubules. This results in delayed recycling of the receptor and a concomitant increase in ␤ 2 AR-dependent endosomal signaling. Thus, ARRDC3 functions as a switch to modulate the endosomal residence time and subsequent intracellular signaling of the ␤ 2 AR.

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Section: Discussionmentioning

confidence: 99%

Section: G Protein-coupled Receptor (Gpcr)mentioning

confidence: 99%

Section: G Protein-coupled Receptor (Gpcr)mentioning

confidence: 99%

Section: Arrdc3 Is Localized On Eea1-positive Early Endosomes Andmentioning

confidence: 99%

See 2 more Smart Citations

The α-Arrestin ARRDC3 Regulates the Endosomal Residence Time and Intracellular Signaling of the β2-Adrenergic Receptor

Tian

Irannejad

Bowman

et al. 2016

Journal of Biological Chemistry

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“…However, the precise role of ARRDC3 in this pathway remains controversial given the dominant role of b-arrestins in regulation of b2AR function (36,38). ARRDC3 possesses arrestin-like N-and C-domains and Cterminal PPxY motifs that bind to WW domains of HECT-domain containing E3 ubiquitin ligases (48,49). Despite the presence of arrestin-like domains, the α-arrestin ARRDC3 appears to lack a polar core, which is essential for β-arrestin binding to activated and phosphorylated GPCRs (50).…”

Section: Discussionmentioning

confidence: 99%

The α-arrestin ARRDC3 suppresses breast carcinoma invasion by regulating G protein–coupled receptor lysosomal sorting and signaling

Arakaki

Pan

Lin

et al. 2018

Journal of Biological Chemistry

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Aberrant G protein-coupled receptor (GPCR) expression and activation has been linked to tumor initiation, progression, invasion and metastasis. However, compared with other cancer drivers, the exploitation of GPCRs as potential therapeutic targets has been largely ignored, despite the fact that GPCRs are highly druggable. Therefore, to advance the potential status of GPCRs as therapeutic targets, it is important to understand how GPCRs function together with other cancer drivers during tumor progression. We now report that the a-arrestin domain-containing protein-3 (ARRDC3) acts as a tumor suppressor in part by controlling signaling and trafficking of the GPCR, protease-activated receptor-1 (PAR1). In a series of highly invasive basal-like breast carcinomas, we found that expression of ARRDC3 is suppressed while PAR1 is aberrantly overexpressed because of defective lysosomal sorting that results in persistent signaling. Using a lentiviral doxycycline-inducible system, we demonstrate that re-expression of ARRDC3 in invasive breast carcinoma is sufficient to restore normal PAR1 trafficking through the ALGinteracting protein X (ALIX)-dependent lysosomal degradative pathway. We also show that ARRDC3 re-expression attenuates PAR1-stimulated persistent signaling of c-Jun NH2-terminal kinase (JNK) in invasive breast cancer. Remarkably, restoration of ARRDC3 expression significantly reduced activated PAR1-induced breast carcinoma invasion, which was also dependent on JNK signaling. These findings are the first to identify a critical link between the tumor suppressor ARRDC3 and regulation of GPCR trafficking and signaling in breast cancer.G protein-coupled receptors (GPCRs) are a large family of cell surface signaling receptors that play a critical role in cancer growth and development by regulating cellular proliferation, invasion, migration, immune cell-mediated functions, angiogenesis and survival at metastatic sites (1-3). GPCR function can be altered in cancer through aberrant overexpression, gain-of-function activating mutations, mutations in downstream G protein signaling effectors, and increased production and secretion of GPCR activating ligands by both tumor cells and surrounding stromal cells (4-7). As cell surface receptors with highly druggable sites, GPCRs are the largest class of drug targets, with over 30% of current FDAhttp://www.jbc.org/cgi

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Phosphorylation of the WWOX Protein Regulates Its Interaction with p73

et al. 2020

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We describe a molecular characterization of the interaction between the cancer‐related proteins WWOX and p73. This interaction is mediated by the first of two WW domains (WW1) of WWOX and a PPXY‐motif‐containing region in p73. While phosphorylation of Tyr33 of WWOX and association with p73 are known to affect apoptotic activity, the quantitative effect of phosphorylation on this specific interaction is determined here for the first time. Using ITC and fluorescence anisotropy, we measured the binding affinity between WWOX domains and a p73 derived peptide, and showed that this interaction is regulated by Tyr phosphorylation of WW1. Chemical synthesis of the phosphorylated domains of WWOX revealed that the binding affinity of WWOX to p73 is decreased when WWOX is phosphorylated. This result suggests a fine‐tuning of binding affinity in a differential, ligand‐specific manner: the decrease in binding affinity of WWOX to p73 can free both partners to form new interactions.

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Structural and Biochemical Basis for Ubiquitin Ligase Recruitment by Arrestin-related Domain-containing Protein-3 (ARRDC3)

Cited by 66 publications

References 37 publications

The α-Arrestin ARRDC3 Regulates the Endosomal Residence Time and Intracellular Signaling of the β2-Adrenergic Receptor

The α-Arrestin ARRDC3 Regulates the Endosomal Residence Time and Intracellular Signaling of the β2-Adrenergic Receptor

The α-arrestin ARRDC3 suppresses breast carcinoma invasion by regulating G protein–coupled receptor lysosomal sorting and signaling

Phosphorylation of the WWOX Protein Regulates Its Interaction with p73

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