The DOI matches its Crossref record; 57 of the 57 references it cites were found in a registry or an index; 5 of the 26 sources its claims cite were checked for support.
Essential Role of Ubiquitin-Specific Protease 8 for Receptor Tyrosine Kinase Stability and Endocytic Trafficking In Vivo
Open accessAbstract
Posttranslational modification by ubiquitin controls multiple cellular functions and is counteracted by the activities of deubiquitinating enzymes. UBPy (USP8) is a growth-regulated ubiquitin isopeptidase that interacts with the HRS-STAM complex. Using Cre-loxP-mediated gene targeting in mice, we show that lack of UBPy results in embryonic lethality, whereas its conditional inactivation in adults causes fatal liver failure. The defect is accompanied by a strong reduction or absence of several growth factor receptor tyrosine kinases (RTKs), like epidermal growth factor receptor, hepatocyte growth factor receptor (c-met), and ERBB3. UBPy-deficient cells exhibit aberrantly enlarged early endosomes colocalizing with enhanced ubiquitination and have reduced levels of HRS and STAM2. Congruently immortalized cells gradually stop proliferation upon induced deletion of UBPy. These results unveil a central and nonredundant role of UBPy in growth regulation, endosomal sorting, and the control of RTKs in vivo.
Overview
AI snapshot
Written from the paper’s full text.
TL;DR
UBPy (USP8) is essential in vivo: constitutive deletion causes embryonic lethality, while induced deletion in adult mice causes fatal liver failure. UBPy maintains receptor tyrosine kinase protein levels and endocytic trafficking, at least in part by counteracting ubiquitination and stabilizing the HRS-STAM complex.
Key findings
- Heterozygote intercrosses yielded 13 UBPy+/+ (27.7%) and 34 UBPy+/− (72.3%) animals but no UBPy−/− mice; E9.5 mutant embryos were growth retarded and disorganized. Adult induced deletion caused death 4 to 6 days after poly(I:C), with severe liver failure, hyperbilirubinemia, and elevated liver enzymes.
- Immortalized UBPy-deficient MEFs stopped growing 6 to 8 days after tamoxifen-induced deletion, with severely reduced BrdU incorporation but no enhanced apoptosis/TUNEL in MEFs; in contrast, hepatocytes showed apoptosis.
- Loss of UBPy strongly reduced or eliminated RTKs: EGFR, c-met, and ERBB3 were decreased/absent in liver extracts, and EGFR was strongly reduced in cells; EGFR mRNA did not differ significantly, and EGF-induced Erk1/2 phosphorylation was impaired, while STAT1 phosphorylation was unaffected.
- UBPy-deficient cells showed enlarged EEA1-positive early endosomes, accumulated multivesicular bodies, reduced/absent HRS and STAM2, and enhanced ubiquitinated substrates colocalizing with enlarged endosomes; proteasomal activity was not impaired and free ubiquitin levels were unchanged, while ALIX and TSG101 were unaffected.
Methods
- Conditional Cre-loxP UBPy mice were generated by flanking exon IV with loxP sites; germline deletion used EIIa-Cre, and adult inducible deletion used MX-Cre with poly(I:C). Embryos were from heterozygous matings.
- Immortalized UBPy fl/fl MEFs expressing Cre-ERT2 were used for tamoxifen-inducible deletion; analyses included immunoblotting, Southern/Northern blotting, immunofluorescence, electron microscopy, BrdU incorporation, TUNEL, liver plasma analysis, and proteasome activity assays.
- EGF stimulation was performed after serum starvation with 100 ng/ml EGF; data are means ± standard errors of the mean, with statistical differences determined by Student’s t test.
Limitations
- The paper states that because of the severe liver phenotype and early death, cell-type-specific inactivation will be necessary to define the physiological relevance in other organs or cell types, and that detailed mechanisms leading to RTK reduction need to be defined.
- The paper notes that MX-Cre-mediated deletion is generally fastest and most efficient in the liver, which most likely explains why the phenotype manifests there although UBPy is also expressed in other cell types.
- Evident from the text: constitutive UBPy loss is embryonic lethal, limiting analysis of adult constitutive deletion; much mechanistic work relies on an immortalized MEF line and induced deletion, and the proposal that UBPy has two independent functions in RTK degradation is presented as a model.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
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Cites
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Verification
Claims the paper makes
5 of 26 cited sources checked · 3 supported · 0 flagged · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In addition, HRS forms a complex with STAM2 (51), which was described as an interaction partner of UBPy (24).”
§ Essential Role of Ubiquitin-Specific Protease 8 for Receptor Tyrosine Kinase Stability and Endocytic Trafficking In Vivo ᰔ † > Induced deletion of UBPy in an immortalized MEF cell line leads to growth arrest.
What the sources say
- Partly supportedcites [51] sourceExperimental — accuracy not yet measured
The Discussion reports that Hbp is closely associated with Hrs in mammalian cells, supporting the complex-formation part of the claim. The sequence-analysis section says Hbp is 53% identical to STAM, but our copy does not identify Hbp as STAM2 or otherwise establish an Hrs–STAM2 complex. No page numbers are available in our copy. (LLM, conf=0.78)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“as HRS-deficient animals also exhibited embryonic lethality caused by ventral-folding defects.”
§ Essential Role of Ubiquitin-Specific Protease 8 for Receptor Tyrosine Kinase Stability and Endocytic Trafficking In Vivo ᰔ † > DISCUSSION
What the sources say
- Partly supportedcites [27] sourceExperimental — accuracy not yet measured
The “Lethality of Hrs mutant embryos” section reports that homozygous mutants die between E10.5 and E11.5, and “Defects in ventral folding morphogenesis” documents their folding defect. The “Role of Hrs in embryonic development” section does not establish that the folding defect caused death; it suggests impaired blood circulation as a possible primary cause. (LLM, conf=0.84)
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes- Partly supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“which has been shown to be essential for this process (6,20)”
§ Essential Role of Ubiquitin-Specific Protease 8 for Receptor Tyrosine Kinase Stability and Endocytic Trafficking In Vivo ᰔ † > DISCUSSION
What the sources say
- Supportedcites [6] source
The Abstract states that HGF/SF/Met signaling is essential for regeneration of the adult liver. The Results and Discussion show that liver regeneration after partial hepatectomy was severely impaired in conditional Met mutant mice, although it could still occur under optimal conditions. (LLM, conf=0.92)
- Not checked — no full text of the sourcecites [20] source
Strength:boosted· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“While this work was in progress, two reports also described endosomal enlargement when UBPy was knocked down by RNA interference (7,48)”
§ Essential Role of Ubiquitin-Specific Protease 8 for Receptor Tyrosine Kinase Stability and Endocytic Trafficking In Vivo ᰔ † > DISCUSSION
What the sources say
- Supportedcites [7] source
The results section reports that UBPY depletion caused dramatic swelling of early and late endosomal structures (Fig. 9). The Experimental Procedures section specifies that UBPY was depleted using siRNA, supporting this paper as one of the reports described. (LLM, conf=0.94)
- Supportedcites [48] source
This paper is one of the reports identified by the two citations. Its Figure 5 caption describes enlarged endosomes after UBPY-specific siRNA treatment, and the Morphological Changes section reports larger multivesicular endosomes in UBPY-depleted cells. Page numbers are not available in the supplied copy. (LLM, conf=0.93)
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes- Supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The observation that UBPy-deficient fibroblasts underwent growth arrest”
- Also stated in: § DISCUSSION · plain
“Impaired proliferation and growth arrest of immortalized cells upon deletion of UBPy.”
§ Essential Role of Ubiquitin-Specific Protease 8 for Receptor Tyrosine Kinase Stability and Endocytic Trafficking In Vivo ᰔ † > DISCUSSION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § DISCUSSION · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the lack of UBPy did not affect STAT-1 phosphorylation upon alpha/beta interferon induction”
§ Essential Role of Ubiquitin-Specific Protease 8 for Receptor Tyrosine Kinase Stability and Endocytic Trafficking In Vivo ᰔ † > Induced deletion of UBPy in an immortalized MEF cell line leads to growth arrest.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“As shown in Fig. 7D, enhanced ubiquitination colocalized with the enlarged early endosomes”
§ Essential Role of Ubiquitin-Specific Protease 8 for Receptor Tyrosine Kinase Stability and Endocytic Trafficking In Vivo ᰔ † > Induced deletion of UBPy in an immortalized MEF cell line leads to growth arrest.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Histological analysis of liver sections revealed that pathological changes started 4 days after the administration of poly(I ⅐ C), as manifested by apoptotic hepatocytes (Councilman bodies) around the central vein (Fig. 3A).”
§ Essential Role of Ubiquitin-Specific Protease 8 for Receptor Tyrosine Kinase Stability and Endocytic Trafficking In Vivo ᰔ † > Embryonic lethality in mice with targeted deletion of UBPy.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“⌬UBPy cells show accumulation of ubiquitinated substrates colocalizing with enlarged early endosomes.”
§ Essential Role of Ubiquitin-Specific Protease 8 for Receptor Tyrosine Kinase Stability and Endocytic Trafficking In Vivo ᰔ † > Induced deletion of UBPy in an immortalized MEF cell line leads to growth arrest.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesThe paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“As loss of UBPy in hepatocytes caused apoptosis and cell death”
§ Essential Role of Ubiquitin-Specific Protease 8 for Receptor Tyrosine Kinase Stability and Endocytic Trafficking In Vivo ᰔ † > DISCUSSION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
- Probably not a substantial claim. 9
- The quote only partly states this claim. 1
- It may state two separate claims as one. 15
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Together, the data provide strong evidence that the death of ⌬UBPy mice is caused by a severe liver failure.”
§ Essential Role of Ubiquitin-Specific Protease 8 for Receptor Tyrosine Kinase Stability and Endocytic Trafficking In Vivo ᰔ † > Embryonic lethality in mice with targeted deletion of UBPy.
Strength:boosted· not yet calibratedCausal:direct· not yet calibratedTests✗ Asserted: fails✓ Checkable: passes✗ Load-bearing: fails✗ Based: failsProbably not a substantial claim. The authors may not put it forward as true. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. The quote only partly states this claim.
- Rests on an assumption: Poly(I:C) administration alone does not cause the lethal liver failure observed in ΔUBPy mice.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“this was not accompanied by reduced cell viability or enhanced apoptosis, as cell numbers did not drop for a period of more than 10 days after growth arrest and the percentage of ⌬UBPy cells staining positive in a TUNEL assay was similar to that of undeleted cells”
§ Essential Role of Ubiquitin-Specific Protease 8 for Receptor Tyrosine Kinase Stability and Endocytic Trafficking In Vivo ᰔ † > Induced deletion of UBPy in an immortalized MEF cell line leads to growth arrest.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Liver injury in mice lacking UBPy was further confirmed by strongly increased serum concentrations of aspartate transaminase and alanine transaminase and was accompanied by higher alkaline phosphatase and gamma-glutamyl-transferase, as well as glutaraldehyde dehydrogenase levels (Fig. 2B).”
§ Essential Role of Ubiquitin-Specific Protease 8 for Receptor Tyrosine Kinase Stability and Endocytic Trafficking In Vivo ᰔ † > Embryonic lethality in mice with targeted deletion of UBPy.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“UBPy Ϫ/Ϫ animals were extremely developmentally retarded and exhibited completely disorganized morphology at that time point.”
§ Essential Role of Ubiquitin-Specific Protease 8 for Receptor Tyrosine Kinase Stability and Endocytic Trafficking In Vivo ᰔ † > DISCUSSION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“c-met, EGFR, and ERBB3 protein levels in ⌬UBPy livers were strongly decreased (c-met) or even below detection levels (EGFR and ERBB3), whereas levels of ␣-integrin and -catenin were unchanged.”
§ Essential Role of Ubiquitin-Specific Protease 8 for Receptor Tyrosine Kinase Stability and Endocytic Trafficking In Vivo ᰔ † > Induced deletion of UBPy in an immortalized MEF cell line leads to growth arrest.
Load-bearingStrength:boosted· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Enlargement of early endosomes, accumulation of MVBs, and reduction of HRS and STAM2 in cells lacking UBPy.”
§ Essential Role of Ubiquitin-Specific Protease 8 for Receptor Tyrosine Kinase Stability and Endocytic Trafficking In Vivo ᰔ † > DISCUSSION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“STAM2 (Hbp), together with Hrs, plays a regulatory role in endocytic trafficking of growth factor receptor complexes through early endosomes (4).”
§ Essential Role of Ubiquitin-Specific Protease 8 for Receptor Tyrosine Kinase Stability and Endocytic Trafficking In Vivo ᰔ † > Abstract
What the sources say
- Not checked — no full text of the sourcecites [4] source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This shows that besides the stabilization of HRS, UBPy is essential for embryonic growth.”
§ Essential Role of Ubiquitin-Specific Protease 8 for Receptor Tyrosine Kinase Stability and Endocytic Trafficking In Vivo ᰔ † > DISCUSSION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Analysis of these mice instead demonstrated an essential role for CYLD in T-cell development (47)”
§ Essential Role of Ubiquitin-Specific Protease 8 for Receptor Tyrosine Kinase Stability and Endocytic Trafficking In Vivo ᰔ † > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites [47] source
Strength:boosted· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These results unveil a central and nonredundant role of UBPy in growth regulation, endosomal sorting, and the control of RTKs in vivo.”
§ Essential Role of Ubiquitin-Specific Protease 8 for Receptor Tyrosine Kinase Stability and Endocytic Trafficking In Vivo ᰔ † > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: Poly(I:C) administration alone does not cause the lethal liver failure observed in ΔUBPy mice.
None of the sources cited for this claim have been checked yet.
In the paper
“Protein levels of UBPy decrease, when cells undergo growth arrest by contact inhibition, suggesting a possible role in the control of mammalian-cell proliferation (40).”
§ Essential Role of Ubiquitin-Specific Protease 8 for Receptor Tyrosine Kinase Stability and Endocytic Trafficking In Vivo ᰔ † > Abstract
What the sources say
- Not checked yetcites [40] source
Checked before — its earlier verdict is held back until a new check runs.
Strength:hedged· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- Not checked yet
None of the sources cited for this claim have been checked yet.
In the paper
“USP8 (UBPy/HUMORF8) was first described as a growthregulated ubiquitin isopeptidase that accumulates upon growth stimulation.”
§ Essential Role of Ubiquitin-Specific Protease 8 for Receptor Tyrosine Kinase Stability and Endocytic Trafficking In Vivo ᰔ † > Abstract
What the sources say
- Not checked yetcites [40] source
Checked before — its earlier verdict is held back until a new check runs.
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Not checked yet
None of the sources cited for this claim have been checked yet.
In the paper
“while HRS-deficient embryos were often as large as wt controls and even had beating hearts by day 9.5 (27)”
§ Essential Role of Ubiquitin-Specific Protease 8 for Receptor Tyrosine Kinase Stability and Endocytic Trafficking In Vivo ᰔ † > DISCUSSION
What the sources say
- Not checked yetcites [27] source
Checked before — its earlier verdict is held back until a new check runs.
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Not checked yet
None of the sources cited for this claim have been checked yet.
In the paper
“It is well documented that upon ligand stimulation RTKs undergo ubiquitin-mediated internalization leading to degradation via the endosomal-lysosomal pathway (13,39).”
§ Essential Role of Ubiquitin-Specific Protease 8 for Receptor Tyrosine Kinase Stability and Endocytic Trafficking In Vivo ᰔ † > Induced deletion of UBPy in an immortalized MEF cell line leads to growth arrest.
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
In the paper
“As a common feature of several RTKs, ligand binding induces ubiquitination as a signal to internalize the receptor via endocytosis (15).”
§ Essential Role of Ubiquitin-Specific Protease 8 for Receptor Tyrosine Kinase Stability and Endocytic Trafficking In Vivo ᰔ † > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites [15] source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
In the paper
“HRS binds directly to ubiquitinated proteins, which are then sorted to clathrin-coated microdomains while nonubiquitinated receptors, like transferrin or LDL receptor, are rapidly recycled to the cell surface (45).”
§ Essential Role of Ubiquitin-Specific Protease 8 for Receptor Tyrosine Kinase Stability and Endocytic Trafficking In Vivo ᰔ † > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites [45] source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“as HRS-deficient murine cells and drosophila HRS Ϫ/Ϫ mutant larvae (27,34) were also reported to exhibit this phenotype.”
§ Essential Role of Ubiquitin-Specific Protease 8 for Receptor Tyrosine Kinase Stability and Endocytic Trafficking In Vivo ᰔ † > DISCUSSION
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The results suggest that UBPy exerts two independent functions in the RTK degradation pathway, first by directly counteracting RTK internalization and second by stabilizing the HRS-STAM complex.”
§ Essential Role of Ubiquitin-Specific Protease 8 for Receptor Tyrosine Kinase Stability and Endocytic Trafficking In Vivo ᰔ † > DISCUSSION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: UBPy functions as a deubiquitinating enzyme (DUB).
None of the sources cited for this claim have been checked yet.
In the paper
“Pathology in the liver can most likely be attributed to the combined effects of disturbed endosomal function, loss of several RTKs, and disturbed liver regeneration caused by the absence of c-met”
§ Essential Role of Ubiquitin-Specific Protease 8 for Receptor Tyrosine Kinase Stability and Endocytic Trafficking In Vivo ᰔ † > DISCUSSION
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“As HRS itself was identified as a protein that is tyrosine phosphorylated upon stimulation with hepatocyte growth factor, platelet-derived growth factor, and epidermal growth factor (26)”
§ Essential Role of Ubiquitin-Specific Protease 8 for Receptor Tyrosine Kinase Stability and Endocytic Trafficking In Vivo ᰔ † > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites [26] source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“This is supported by results from Mizuno et al., who described a direct interaction of UBPy and the EGFR resulting in EGFR deubiquitination (38).”
§ Essential Role of Ubiquitin-Specific Protease 8 for Receptor Tyrosine Kinase Stability and Endocytic Trafficking In Vivo ᰔ † > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites [38] source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The results are compatible with a model in which UBPy counteracts ubiquitination of RTKs or components of the endocytic machinery and thus regulates thresholds for the internalization of growth factor receptors.”
§ Essential Role of Ubiquitin-Specific Protease 8 for Receptor Tyrosine Kinase Stability and Endocytic Trafficking In Vivo ᰔ † > DISCUSSION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: UBPy functions as a deubiquitinating enzyme (DUB).
The paper relies on this without support.
Poly(I:C) administration alone does not cause the lethal liver failure observed in ΔUBPy mice.
“Mutant mice with the induced deletion of UBPy (⌬UBPy mice) died 4 to 6 days after the administration of poly(I ⅐ C)”
The paper relies on this without support.
UBPy functions as a deubiquitinating enzyme (DUB).
“Consistent with the function of UBPy as a DUB”
The paper relies on this without support.
UBPy is expressed in other cell types.
“although UBPy is also expressed in other cell types.”
The paper relies on this without support.
MVB maturation is a prerequisite of RTK degradation via the lysosomal pathway.
“a prerequisite of RTK degradation via the lysosomal pathway.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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 [24]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“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 [24]
In the citing paper
“An essential growth-regulated enzyme, USP8, is indispensable to cellular proliferation and survival (23,24).”
From Regulation of Epidermal Growth Factor Receptor Ubiquitination and Trafficking by the USP8·STAM Complex (2010) · cites this paper as [24]
In the citing paper
“Analysis of a conditional USP8 mouse knock-out has revealed a drastic loss of growth factor receptors, including the EGFR, its family member, Erb-B3, and c-Met (24).”
From Regulation of Epidermal Growth Factor Receptor Ubiquitination and Trafficking by the USP8·STAM Complex (2010) · cites this paper as [24]
In the citing paper
“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 [24]
In the citing paper
“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 [24]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Mutant mice reported dead before day-7 sampling
MajorThe results state that mice with induced UBPy deletion died 4 to 6 days after poly(I 1⁄7 C) administration, but the Figure 2 caption says plasma was collected from 12 such mice seven days after induction.
“Mutant mice with the induced deletion of UBPy (⌬UBPy mice) died 4 to 6 days after the administration of poly(I ⅐ C), demonstrating an essential, nonredundant function of UBPy in vivo (Fig. 2A).”
“Seven days after poly(I ⅐ C) induction, plasmas of 10 UBPY ϩ/ϩ MX-Cre ϩ controls (open bars) and 12 UBPY fl/fl MX-Cre ϩ (⌬UBPy; solid bars) mice were analyzed.”
Citations
Cites
Mechanisms Underlying Ubiquitination
Pickart, C. M. (2001) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.70.1.503 · Cited by 3,184
A genomic and functional inventory of deubiquitinating enzymes.
Nijman, S. M. B., Luna-Vargas, M. P. A., Velds, A., Brummelkamp, T. R., Dirac, A. M. G., Sixma, T. K., & Bernards, R. (2005) · Cell · doi:10.1016/j.cell.2005.11.007 · Cited by 1,854
Inducible Gene Targeting in Mice
Kühn, R., Schwenk, F., Aguet, M., & Rajewsky, K. (1995) · Science · doi:10.1126/science.7660125 · Cited by 1,641
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Endocytosis and signalling: intertwining molecular networks
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Deubiquitylating enzymes and drug discovery: emerging opportunities
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Metadata
- Authors
- Niendorf, S., Oksche, A., Kisser, A., Löhler, J., Prinz, M., Schorle, H., Feller, S., Lewitzky, M., Horak, I., & Knobeloch, K.-P.
- Affiliations
- Leibniz-Forschungsinstitut für Molekulare Pharmakologie (DE)
- Charité – Universitätsmedizin Berlin (DE)
- Leibniz Institute of Virology (LIV) (DE)
- University of Göttingen (DE)
- University of Bonn (DE)
- Cancer Research UK (GB)
- ORCID
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2007-07-01
- Volume
- 27
- Issue
- 13
- Pages
- 5029-5039
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC1951504
- OpenAlex
- W2069862324
- Semantic Scholar
- d85383238b90e64900ed63aa21883f499b7c3b68
- Cited by
- 207
- References
- 56
- Citations by year
- 2026: 8 · 2025: 9 · 2024: 13 · 2023: 9 · 2022: 7 · 2021: 9 · 2020: 9 · 2019: 10 · 2018: 15 · 2017: 9 · 2016: 9 · 2015: 17 · 2014: 9 · 2013: 14 · 2012: 10
- FWCI
- 4.13
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Informationszentrum Lebenswissenschaften (ZB MED) (submittedVersion)
- GRO (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Keywords
- USP8, receptor tyrosine kinase, receptor stability, endosomal trafficking, STAM2, early endosomes, ubiquitination, epidermal growth factor receptor, c-Met, HER3, liver failure, embryonic lethality, growth regulation, cell proliferation
- MeSH terms
- Animals, Cell Line, Transformed, Death, Embryo, Mammalian, Endocytosis, Enzyme Stability, Fibroblasts, Humans, Liver, Endopeptidases, Endosomes, Mutagenesis, Gene Deletion, Gene Targeting, Proto-Oncogene Proteins c-met, Receptor Protein-Tyrosine Kinases, Receptor, ErbB-3, Ubiquitin, Ubiquitin Thiolesterase, Multiprotein Complexes, Cell Proliferation, Mice, Endosomal Sorting Complexes Required for Transport, ErbB Receptors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-11-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-11-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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