UBE4B Protein Couples Ubiquitination and Sorting Machineries to Enable Epidermal Growth Factor Receptor (EGFR) Degradation

Sirisaengtaksin, Natalie; Gireud, Monica; Yan, Qing; Kubota, Yoshihisa; Meza, Denisse; Waymire, Jack C.; Zage, Peter E.; Bean, Andrew J.

doi:10.1074/jbc.m113.495671

Cited by 45 publications

(48 citation statements)

References 54 publications

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“…In cell-free assays performed as previously described [35,36], internalization of the FGFR4 Arg388 variant into internal MVB vesicles was reduced compared to the FGFR4 Gly388 variant in endosomes isolated from HEK 293T cells and from SK-N-AS cells, although the reduction observed in SK-N-AS cells did not reach statistical significance (Figure 3). This decreased internalization of the FGFR4 Arg388 variant into internal MVB vesicles may explain, at least in part, the observed reduction in degradation and may provide a mechanistic link to the increased prevalence of neuroblastoma seen in children with the FGFR4 Arg388 polymorphism.…”

Section: Resultsmentioning

confidence: 78%

“…We have previously shown that UBE4B plays a crucial role in GFR trafficking and degradation in neuroblastoma tumor cells, suggesting a previously uncharacterized link between GFR trafficking and degradation and tumorigenesis [36,37]. Dysregulation of GFR trafficking is clearly emerging as an important mechanism for oncogenesis in a variety of human cancers.…”

Section: Discussionmentioning

confidence: 99%

“…The cell-free reconstitution of multivesicular body (MVB) formation and receptor sorting was performed as previously described [35,36]. Cells transfected with vectors encoding either V5-tagged FGFR4 Arg388 or FGFR4 Gly388 were serum-starved (1% Bovine Serum Albumin and 30 μg/mL cycloheximide in media) for 2 hours and stimulated with 50 ng/mL bFGF (with 30 μg/mL cycloheximide) in media for 6 hours.…”

Section: Methodsmentioning

confidence: 99%

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A Polymorphism in the FGFR4 Gene Is Associated With Risk of Neuroblastoma and Altered Receptor Degradation

Whittle

Reyes-Esteves

et al. 2016

Journal of Pediatric Hematology/Oncology

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Background Outcomes for children with high-risk neuroblastoma are poor, and improved understanding of the mechanisms underlying pathogenesis, recurrence and treatment resistance will lead to improved outcomes. Aberrant growth factor receptor expression and receptor tyrosine kinase signaling are associated with the pathogenesis of many malignancies. A germline polymorphism in the FGFR4 gene is associated with increased receptor expression and activity and with decreased survival, treatment resistance, and aggressive disease for many malignancies. We therefore investigated the role of this FGFR4 polymorphism in neuroblastoma pathogenesis. Methods Germline DNA from neuroblastoma patients and matched controls was assessed for the FGFR4 Gly/Arg388 polymorphism by RT-PCR. Allele frequencies were assessed for association with neuroblastoma patient outcomes and prognostic features. Degradation rates of the FGFR4 Arg388 and Gly388 receptors and rates of receptor internalization into the late endosomal compartment were measured. Results Frequency of the FGFR4 AA genotype and the prevalence of the A allele were significantly higher in patients with neuroblastoma than in matched controls. The Arg388 receptor demonstrated slower degradation than the Gly388 receptor in neuroblastoma cells and reduced internalization into multi-vesicular bodies. Conclusions The FGFR4 Arg388 polymorphism is associated with an increased prevalence of neuroblastoma in children, and this association may be linked to differences in FGFR4 degradation rates. Our study provides the first evidence of a role for FGFR4 in neuroblastoma, suggesting that FGFR4 genotype and the pathways regulating FGFR4 trafficking and degradation may be relevant for neuroblastoma pathogenesis.

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Section: Resultsmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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A Polymorphism in the FGFR4 Gene Is Associated With Risk of Neuroblastoma and Altered Receptor Degradation

Whittle

Reyes-Esteves

et al. 2016

Journal of Pediatric Hematology/Oncology

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“…The role of Ub in lysosomal degradation is extensive; therefore it is conceptually attractive to consider deubiqutintating peptidases (DUbs) as potential and permissive facilitators of recycling simply for their ability to intentionally antagonize the signals for lysosomal degradation (Figure 2). This has been documented for the Epidermal Growth Factor Receptor (EGFR), where deubiquitnating activity of AMSH, USP8, and Cezanne-1 serve to attenuate receptor turnover [18-21] allowing EGFR to repopulate the cell surface [22]. Yet, the effects of perturbing these DUbs can be explained by the possibility they regulate the sorting machinery itself rather than deubiquitinating cargo per se .…”

Section: Deubiquitnation As a Trigger For Recyclingmentioning

confidence: 99%

Cell surface recycling in yeast: mechanisms and machineries

MacDonald

Piper

2016

Biochemical Society Transactions

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Sorting internalized proteins and lipids back to the cell surface controls the supply of molecules throughout the cell and regulates integral membrane protein activity at the surface. One central process in mammalian cells is the transit of cargo from endosomes back to the plasma membrane directly, along a route that bypasses retrograde movement to the Golgi. Despite recognition of this pathway for decades we are only beginning to understand the machinery controlling this overall process. Saccharomyces cerevisiae, a stalwart genetic system that has routinely helped identify key proteins and mechanisms for other fundamental trafficking steps, presents several obstacles that obscure the study of recycling, particularly through early endosomes. Here we briefly discuss how recycling could be a more prevalent process in yeast than is widely appreciated and how tools might be built to better study it.

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“…USP8 degrades Lys-48-, Lys-63-, and Lys-6-linked ubiquitin chains (26,27). USP8 has been shown to negatively regulate the ubiquitination of lysosome-degraded proteins, including the epidermal growth factor receptor (EGFR) (23,28,29); tropomyosin-related kinase A (TRKA) (25); AMPA receptor (30); vascular endothelial growth factor receptor 2 (VEGFR2) (31); leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) (32); potassium intermediate/small conductance calcium-activated channel, subfamily N, member 4 (KCA3.1) (33); proteaseactivated receptor 2 (PAR2) (34); and ␦-opioid receptor (35).…”

mentioning

confidence: 99%

The Endosome-associated Deubiquitinating Enzyme USP8 Regulates BACE1 Enzyme Ubiquitination and Degradation

Yeates¹,

Tesco

2016

Journal of Biological Chemistry

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The ␤-site amyloid precursor protein-cleaving enzyme (BACE1) is the rate-limiting enzyme in the production of amyloid-␤, the toxic peptide that accumulates in the brain of subjects affected by Alzheimer disease. Our previous studies have shown that BACE1 is degraded via the lysosomal pathway and that that depletion of the trafficking molecule Golgi-localized ␥-ear-containing ARF-binding protein 3 (GGA3) results in increased BACE1 levels and activity because of impaired lysosomal degradation. We also determined that GGA3 regulation of BACE1 levels requires its ability to bind ubiquitin. Accordingly, we reported that BACE1 is ubiquitinated at lysine 501 and that lack of ubiquitination at lysine 501 produces BACE1 stabilization. Ubiquitin conjugation is a reversible process mediated by deubiquitinating enzymes. The ubiquitin-specific peptidase 8 (USP8), an endosome-associated deubiquitinating enzyme, regulates the ubiquitination, trafficking, and lysosomal degradation of several plasma membrane proteins. Here, we report that RNAi-mediated depletion of USP8 reduced levels of both ectopically expressed and endogenous BACE1 in H4 human neuroglioma cells. Moreover, USP8 depletion increased BACE1 ubiquitination, promoted BACE1 accumulation in the early endosomes and late endosomes/lysosomes, and decreased levels of BACE1 in the recycling endosomes. We also found that decreased BACE1 protein levels were accompanied by a decrease in BACE1-mediated amyloid precursor protein cleavage and amyloid-␤ levels. Our findings demonstrate that USP8 plays a key role in the trafficking and degradation of BACE1 by deubiquitinating lysine 501. These studies suggest that therapies able to accelerate BACE1 degradation (e.g. by increasing BACE1 ubiquitination) may represent a potential treatment for Alzheimer disease.

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UBE4B Protein Couples Ubiquitination and Sorting Machineries to Enable Epidermal Growth Factor Receptor (EGFR) Degradation

Cited by 45 publications

References 54 publications

A Polymorphism in the FGFR4 Gene Is Associated With Risk of Neuroblastoma and Altered Receptor Degradation

A Polymorphism in the FGFR4 Gene Is Associated With Risk of Neuroblastoma and Altered Receptor Degradation

Cell surface recycling in yeast: mechanisms and machineries

The Endosome-associated Deubiquitinating Enzyme USP8 Regulates BACE1 Enzyme Ubiquitination and Degradation

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