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Regulation of Epidermal Growth Factor Receptor Down-Regulation by UBPY-mediated Deubiquitination at Endosomes
Abstract
Ligand-activated receptor tyrosine kinases undergo endocytosis and are transported via endosomes to lysosomes for degradation. This “receptor down-regulation” process is crucial to terminate the cell proliferation signals produced by activated receptors. During the process, ubiquitination of the receptors serves as a sorting signal for their trafficking from endosomes to lysosomes. Here, we describe the role of a deubiquitinating enzyme UBPY/USP8 in the down-regulation of epidermal growth factor (EGF) receptor (EGFR). Overexpression of UBPY reduced the ubiquitination level of EGFR and delayed its degradation in EGF-stimulated cells. Immunopurified UBPY deubiquitinated EGFR in vitro. In EGF-stimulated cells, UBPY underwent ubiquitination and bound to EGFR. Overexpression of Hrs or a dominant-negative mutant of SKD1, proteins that play roles in the endosomal sorting of ubiquitinated receptors, caused the accumulation of endogenous UBPY on exaggerated endosomes. A catalytically inactive UBPY mutant clearly localized on endosomes, where it overlapped with EGFR when cells were stimulated with EGF. Finally, depletion of endogenous UBPY by RNA interference resulted in elevated ubiquitination and accelerated degradation of EGF-activated EGFR. We conclude that UBPY negatively regulates the rate of EGFR down-regulation by deubiquitinating EGFR on endosomes.
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USP8 is a deubiquitinating enzyme not previously implicated in mitochondrial quality control.
“USP8/UBPY, a deubiquitinating enzyme not previously implicated in mitochondrial quality control, is critical for parkin-mediated mitophagy.”
From USP8 regulates mitophagy by removing K6‐linked ubiquitin conjugates from parkin (2014) · cites this paper as Mizuno et al, 2005
USP8 does not exhibit intrinsic linkage selectivity when Ub chains are not attached to parkin; it cleaves K6-, K11-, K48-, and K63-linked free di-Ub.
“USP8 did not appear to exhibit intrinsic linkage selectivity when the Ub chains were not attached to parkin, as it could efficiently cleave K6-, K11-, K48-, and K63-linked free di-Ub”
From USP8 regulates mitophagy by removing K6‐linked ubiquitin conjugates from parkin (2014) · cites this paper as Mizuno et al, 2005
USP8 likely acts on ubiquitylated LDLR directly and shunts it away from degradation.
“Likely, USP8 acts on ubiquitylated LDLR directly and shunts it away from degradation, as has been shown in the case of the EGFR ( 52 ).”
From The LXR-IDOL axis defines a clathrin-, caveolae-, and dynamin-independent endocytic route for LDLR internalization and lysosomal degradation (2013) · cites this paper as [52]
Overexpression of wild-type USP8 diminishes EGFR ubiquitination.
“whereas overexpression of wild type enzyme led to diminished receptor ubiquitination (Ref.27 and Fig. 2C (representative data are shown in Fig. 6A)).”
From Regulation of Epidermal Growth Factor Receptor Ubiquitination and Trafficking by the USP8·STAM Complex (2010) · cites this paper as [27]
USP8/UBPy has been previously implicated in the regulation of EGFR.
“The deubiquitinating enzyme ubiquitin-specific protease 8 (USP8/UBPy) has been previously implicated in the regulation of the epidermal growth factor receptor (EGFR); however, the molecular mechanisms governing its recruitment and activity in this context remain unclear.”
From Regulation of Epidermal Growth Factor Receptor Ubiquitination and Trafficking by the USP8·STAM Complex (2010) · cites this paper as [27]
USP8 inactivation leads to enhanced ubiquitination of EGFR in response to ligand-induced activation.
“Consistent with these findings, USP8 inactivation leads to enhanced ubiquitination of EGFR in response to ligand-induced activation (26,27)”
From Regulation of Epidermal Growth Factor Receptor Ubiquitination and Trafficking by the USP8·STAM Complex (2010) · cites this paper as [27]
The current consensus in the literature indicates that USP8 functions to protect EGFR from ligand-induced down-regulation by direct deubiquitination of activated receptors.
“The current consensus in the literature indicates that USP8 functions to protect EGFR from ligand-induced down-regulation by virtue of direct deubiquitination of activated receptors (24,27,41).”
From Regulation of Epidermal Growth Factor Receptor Ubiquitination and Trafficking by the USP8·STAM Complex (2010) · cites this paper as [27]
Cellular distribution of USP8 straddles the endosomal continuum between early and late extremes.
“cellular distribution of USP8 has been reported to straddle the endosomal continuum between the early and late extremes (27,34,35)”
From Regulation of Epidermal Growth Factor Receptor Ubiquitination and Trafficking by the USP8·STAM Complex (2010) · cites this paper as [27]
Our loss-of-function studies indicate a requirement for USP8 in EGFR stabilization and demonstrate that accelerated receptor degradation resulting from USP8 depletion proceeds through a pathway controlled by Hrs.
“In agreement with published evidence, our loss-of-function studies indicate a requirement for USP8 in EGFR stabilization (24,27,41) and demonstrate that accelerated receptor degradation, resulting from USP8 depletion, proceeds through a pathway controlled by Hrs (Fig. 1).”
From Regulation of Epidermal Growth Factor Receptor Ubiquitination and Trafficking by the USP8·STAM Complex (2010) · cites this paper as [27]
AMSH does not directly regulate EGFR but functions to generally promote cargo trafficking through the sorting endosome.
“Unlike AMSH, which does not directly regulate EGFR (27) but functions to generally promote cargo trafficking through the sorting endosome (48)”
From Regulation of Epidermal Growth Factor Receptor Ubiquitination and Trafficking by the USP8·STAM Complex (2010) · cites this paper as [27]
USP8 is required to deubiquitinate and protect EGFR from lysosomal degradation.
“USP8 is required to deubiquitinate and, thus, protect EGFR from lysosomal degradation (24,27,41).”
From Regulation of Epidermal Growth Factor Receptor Ubiquitination and Trafficking by the USP8·STAM Complex (2010) · cites this paper as [27]
UBPy directly interacts with EGFR resulting in EGFR deubiquitination.
“This is supported by results from Mizuno et al., who described a direct interaction of UBPy and the EGFR resulting in EGFR deubiquitination (38).”
From Essential Role of Ubiquitin-Specific Protease 8 for Receptor Tyrosine Kinase Stability and Endocytic Trafficking In Vivo (2007) · cites this paper as [38]
USP8 overexpression reduces degradation of the EGF receptor.
“USP8 overexpression reduces degradation of the EGF receptor (36”
From Ubiquitin-specific Peptidase 8 (USP8) Regulates Endosomal Trafficking of the Epithelial Na+ Channel* (2013) · cites this paper as [36]
USP8 deubiquitinates additional membrane proteins, with complex functional effects.
“USP8 has been shown to deubiquitinate additional membrane proteins, although the functional effects of deubiquitination are complex.”
From Ubiquitin-specific Peptidase 8 (USP8) Regulates Endosomal Trafficking of the Epithelial Na+ Channel* (2013) · cites this paper as [36]
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Metadata
- Authors
- Mizuno, E., Iura, T., Mukai, A., Yoshimori, T., Kitamura, N., & Komada, M.
- Venue
- Molecular Biology of the Cell
- Published
- 2005-11
- Volume
- 16
- Issue
- 11
- Pages
- 5163-5174
- ISSN
- 1059-1524
- 1939-4586
- Cited by
- 248
- References
- 1
- Language
- en
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