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Adaptor protein Disabled-2 modulates low density lipoprotein receptor synthesis in fibroblasts from patients with autosomal recessive hypercholesterolaemia
Open accessAbstract
Autosomal recessive hypercholesterolaemia (ARH), characterized clinically by severe inherited hypercholesterolaemia, is caused by recessive null mutations in LDLRAP1 (formerly ARH). Immortalized lymphocytes and monocyte-macrophages, and presumably hepatocytes, from ARH patients fail to take up and degrade plasma low density lipoproteins (LDL) because they lack LDLRAP1, a cargo-specific adaptor required for clathrin-mediated endocytosis of the LDL receptor. Surprisingly, LDL-receptor function is normal in ARH patients' skin fibroblasts in culture. Disabled-2 (Dab2) has been implicated previously in clathrin-mediated internalization of LDL-receptor family members, and we show here that Dab2 is highly expressed in skin fibroblasts, but not in lymphocytes. SiRNA-depletion of Dab2 profoundly reduced LDL-receptor activity in ARH fibroblasts as a result of profound reduction in LDL-receptor protein, but not mRNA; heterologous expression of murine Dab2 reversed this effect. In contrast, LDL-receptor protein content was unchanged in Dab-2-depleted control cells. Incorporation of 35S-labelled amino acids into LDL receptor protein revealed a corresponding apparent reduction in accumulation of newly synthesized LDL-receptor protein on depletion of Dab2 in ARH, but not in control, cells. This reduction in LDL-receptor protein in Dab2-depleted ARH cells could not be reversed by treatment of the cells with proteasomal or lysosomal inhibitors. Thus, we propose a novel role for Dab2 in ARH fibroblasts, where it is apparently required to allow normal translation of LDL receptor mRNA.
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Written from the paper’s full text.
TL;DR
In ARH fibroblasts lacking LDLRAP1, siRNA depletion of Dab2 markedly reduces LDL-receptor protein and LDL uptake, while control fibroblasts are largely unaffected. The data suggest Dab2 is required in ARH fibroblasts for normal LDL-receptor synthesis, likely at the level of translation, rather than for LDL-receptor internalization.
Key findings
- Dab2 protein was highly expressed in cultured normal skin fibroblasts but barely detectable in normal EBV-lymphocytes; LDLRAP1 was detectable in both cell types.
- Dab2 depletion in ARH fibroblasts reduced saturable 125I-LDL uptake to 28 ± 4% of non-targeting siRNA controls, whereas control fibroblasts showed only a slight reduction to 86 ± 2%; degradation reflected uptake.
- Dab2 depletion reduced LDL-receptor protein by up to 75% in ARH cells but little or not at all in control cells; LDL-receptor mRNA was unchanged, and expression of murine Dab2-GFP restored LDL-receptor protein in 28 counted cells, whereas GFP alone did not restore it in any of 32 cells.
- 35S-labelled amino acid incorporation into mature LDL receptor in Dab2-depleted ARH cells was 45.2 ± 18.9% of control siRNA at 4 h chase and 33.5 ± 14.7% at 8 h chase; corresponding control-cell values were 91.3 ± 4.7% and 93.8 ± 2.8%. Proteasomal or lysosomal inhibitors did not reverse the reduction.
Methods
- Cultured human skin fibroblasts from control subjects and ARH patients, EBV-transformed lymphocytes, and CHO ldlA7 cells were used; ARH fibroblasts included cells homozygous for Q136X or W22X and cells heterozygous for a large deletion of approximately exons 6–9 and insC620.
- Dab2 and AP2-α were depleted with siRNA; effects were assessed by immunoblotting, quantitative real-time RT-PCR for LDL-receptor mRNA, confocal microscopy, 125I-LDL uptake and degradation assays, 125I-transferrin uptake assays, and 35S-methionine/cysteine pulse-chase immunoprecipitation of LDL receptor.
- Main comparisons were between non-targeting siRNA and Dab2 or AP2-α siRNA in control versus ARH fibroblasts, with densitometry and phosphorimaging quantification.
Limitations
- The authors state that their original aim—determining whether Dab2 facilitates LDL-receptor internalization in ARH fibroblasts—could not be resolved from their data because LDL-receptor protein was reduced.
- The authors state they cannot exclude the possibility that proteolytic pathways were induced that were unaffected by the protease inhibitors tested, and they note that extensive studies will be required to address the mechanism.
- The authors report that precursor conversion could not be accurately quantified in Dab2-depleted ARH cells because radioactivity in precursor bands was insufficient; the text also makes evident that key experiments used fibroblasts from two control subjects and two ARH patients, and that AP2-α knockdown was incomplete.
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- Findingown data
Depletion of Dab2 in control fibroblasts resulted in a slight reduction in uptake of 125I-LDL to 86±2% of that in cells transfected with a non-targeting siRNA.
“In three separate experiments, depletion of Dab2 in control fibroblasts resulted in a slight reduction in uptake of LDL to 86 + 2% of that in cells transfected with a non-targeting siRNA (Fig. 2A, filled triangles versus filled circles).”
Quote in the paperSubstantial claim - Findingown data
The rate of incorporation of 35S-labelled amino acids into LDL-receptor protein was greatly reduced in Dab2-depleted ARH cells.
“However, the rate of incorporation of 35 S-labelled amino acids into LDL-receptor protein was greatly reduced in Dab2-depleted ARH cells (Fig. 4D, compare open and closed symbols).”
Quote in the paperSubstantial claim - Findingown data
Treatment of ARH cells with proteasomal inhibitor MG132 (20 mM for 8 h) or solvent vehicle DMSO had no influence on LDL-receptor protein content of ARH cells treated with control siRNA or cells depleted of Dab2.
“As shown in Figure 5A, treatment of ARH cells with the proteasomal inhibitor MG132 (20 mM for 8 h) or the equivalent volume of solvent vehicle DMSO, as indicated above the gel image, had no influence on the LDL-receptor protein content of ARH cells treated with control siRNA, (left two lanes) or cells depleted of Dab2 (right two lanes).”
Quote in the paperSubstantial claim - Findingown data
Over-expression of a murine Dab2 construct not targeted by the siRNA reversed the loss of LDL receptor protein in these cells.
“We confirmed this by our observation that over-expression of a murine Dab2 construct not targeted by the siRNA reversed the loss of LDL receptor protein in these cells.”
Quote in the paperSubstantial claim - Findingown data
Incubation of siRNA-treated ARH cells with leupeptin (100mM for 20 h) had no effect on LDL receptor protein content.
“To determine whether other protease inhibitors had any effect on LDL receptor protein content in Dab2-depleted ARH cells, we also incubated siRNA-treated ARH cells with leupeptin (100mM for 20 h) and found no effect (Fig. 5C, compare lanes 7 and 8).”
Quote in the paperNot a substantial claim
- Findingown data
The AP2 knockdown was sufficient to reduce Tf uptake in the same cells to a negligible level.
“it was sufficient to reduce Tf uptake in the same cells to a negligible level (Fig. 6).”
Quote in the paperSubstantial claim - Findingown data
No accumulation of precursor protein was evident in the Dab2-depleted ARH cells.
“In our study, no accumulation of precursor protein was evident in the Dab2-depleted ARH cells (Fig. 4), which might have been explained by its rapid degradation in the ER due to lack of protection by Dab2.”
Quote in the paperSubstantial claim - Findingown data
In pulse-chase experiments, profound depletion of Dab2 in control cells had little discernible effect on either the rate of synthesis of mature LDL-receptor protein or its subsequent turnover during the chase period.
“As seen from the gel shown in Figure 4A (compare upper and lower panels) and the quantified radioactivity (Fig. 4C, compare open and closed symbols), profound depletion of Dab2 in control cells had little discernable effect on either the rate of synthesis of mature LDL-receptor protein or its subsequent turnover during the chase period.”
Quote in the paperSubstantial claim - Findingown data
Incubation of CHO cells expressing mutant LDL receptor I402T and C240F with MG132 resulted in expected increased accumulation of the mutant proteins.
“As shown in Fig. 5B, incubation of these cells with MG132 resulted in the expected increased accumulation of the mutant proteins.”
Quote in the paperSubstantial claim - Findingown data
Depletion of Dab2 in ARH fibroblasts reduced uptake of 125I-LDL to 28±4% of that in cells transfected with a non-targeting siRNA.
“In contrast, depletion of Dab2 in the ARH fibroblasts rendered the cells essentially unable to take up 125 I-LDL, reducing uptake to 28 + 4% of that in cells transfected with a non-targeting siRNA (Fig. 2B).”
Quote in the paperSubstantial claim - Findingown data
Confocal microscopy of immunolabelled cells showed no evidence for accumulation of LDL receptor protein on the surface of fibroblasts lacking Dab2 and LDLRAP1.
“Our data from confocal microscopy of immunolabelled cells showed no evidence for accumulation of LDL receptor protein on the surface of fibroblasts lacking Dab2 and LDLRAP1 (Fig. 3C)”
Quote in the paperSubstantial claim - Findingown data
Depletion of AP2-a had little or no effect on LDL-receptor protein in either control or ARH cells.
“Depletion of AP2-a had little or no effect on LDL-receptor protein in either control or ARH cells.”
Quote in the paperSubstantial claim - Findingown data
The reduction in LDL-receptor protein was not secondary to a reduction in LDL-receptor mRNA content of the cells, as quantitative RT-PCR revealed no significant differences in LDL-receptor mRNA levels between control and ARH fibroblasts.
“The reduction in LDL-receptor protein was not secondary to a reduction in LDL-receptor mRNA content of the cells, as quantitative RT -PCR revealed no significant differences in LDL-receptor mRNA levels between control and ARH fibroblasts.”
Quote in the paperSubstantial claim - Findingnone given
LDL-receptor protein is unstable in ARH skin fibroblasts depleted of Dab2.
“but is unstable in ARH skin fibroblasts depleted of Dab2 is puzzling.”
Quote in the paperSubstantial claim - Findingown data
The effect of AP2 depletion on LDL uptake in ARH fibroblasts was much less profound than that caused by Dab2 depletion.
“However, the observed effect was much less profound than that caused by Dab2 depletion (Fig. 2B).”
Quote in the paperSubstantial claim - Findingown data
Both these parameters were indistinguishable from those in ARH cells treated with the control siRNA.
“Furthermore, both these parameters were indistinguishable from those in ARH cells treated with the control siRNA (Fig. 4B, compare upper panel with control cells in Fig. 4A, and in Fig. 4D, compare closed symbols with Fig. 4C).”
Quote in the paperSubstantial claim - Findingown data
In ARH fibroblasts lacking LDLRAP1, depletion of the a-subunit of AP2 slightly impaired LDL uptake.
“when we depleted the a-subunit of AP2 in ARH fibroblasts which lack LDLRAP1, LDL uptake was slightly impaired while LDL-receptor protein levels were unchanged (Figs 2 and 3A).”
Quote in the paperSubstantial claim - Findingown data
LDLRAP1 is detectable in both normal skin fibroblasts and EBV-lymphocytes.
“In contrast, LDLRAP1 was detectable in both cell types (Fig. 1B).”
Quote in the paperNot a substantial claim - Findingown data
In ARH fibroblasts lacking LDLRAP1, depletion of the a-subunit of AP2 did not change LDL-receptor protein levels.
“when we depleted the a-subunit of AP2 in ARH fibroblasts which lack LDLRAP1, LDL uptake was slightly impaired while LDL-receptor protein levels were unchanged (Figs 2 and 3A).”
Quote in the paperSubstantial claim - Findingown data
Depletion of AP2 with siRNA directed to a-adaptin subunit strongly reduced uptake of 125I-Tf in both control and ARH fibroblasts to <26% of that in cells transfected with non-targeting siRNA.
“As expected, depletion of AP2 with siRNA directed to the a-adaptin subunit strongly reduced the uptake of 125 I-Tf in both control and ARH fibroblasts to ,26% of that in cells transfected with a non-targeting siRNA (Fig. 6, open triangles).”
Quote in the paperSubstantial claim - Findingown data
The reduction in LDL-receptor protein is not caused by reduced transcription.
“Since the reduction in LDL-receptor protein is not caused by reduced transcription”
Quote in the paperSubstantial claim - Findingown data
Tf uptake in control cells was not affected by depletion of Dab2.
“although Tf uptake in control cells was not affected by depletion of Dab2”
Quote in the paperNot a substantial claim - Findingown data
Changing conditions or incubation with other protease inhibitors (ammonium chloride, lactacystin, ALLN) did not result in any increase in LDL-receptor protein in Dab2-depleted ARH cells.
“Chan-ging the conditions (concentration of inhibitor or time of incubation) according to published reports (21 -23) did not result in any increase in LDL-receptor protein in Dab2-depleted ARH cells, nor did incubation with other protease inhibitors, i.e. ammonium chloride, lactacystin or ALLN (data not shown).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [21]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [22]
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- cites [23]
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- Findingown data
Transfection of control fibroblasts with siRNA targeted to the a-subunit of AP2 did not impair LDL uptake.
“We transfected control fibroblasts with siRNA targeted to the a-subunit of AP2 and found that LDL uptake was not impaired (Fig. 2).”
Quote in the paperSubstantial claim - Findingown data
Knockdown of AP2 achieved by a-adaptin siRNA was incomplete.
“Although the knockdown of AP2 achieved by the a-adaptin siRNA was incomplete (Fig. 1)”
Quote in the paperNot a substantial claim - Findingown data
ARH cells depleted of Dab2 contained no detectable LDL-receptor protein, either inside the cell or on the cell surface.
“ARH cells depleted of Dab2 contained no detectable LDLreceptor protein, either inside the cell or on the cell surface (Fig. 3C).”
Quote in the paperSubstantial claim - Findingown data
EBV-transformed lymphocytes from ARH patients do not express detectable Dab2.
“which, as we have shown here, do not express detectable Dab2 (Fig. 1)”
Quote in the paperSubstantial claim - Findingown data
Tf uptake was slightly less efficient in Dab2-depleted, LDLRAP1-deficient cells.
“it was slightly less efficient in Dab2-depleted, LDLRAP1-deficient cells”
Quote in the paperNot a substantial claim - Findingown data
The reduction in LDL-receptor protein cannot be rescued by proteasomal or lysosomal inhibitors under the conditions tried.
“cannot be rescued by proteasomal or lysosomal inhibitors under the conditions we have tried”
Quote in the paperSubstantial claim - Findingown data
Similar results were obtained when the amount of LDL-receptor mRNA was expressed relative to 18S rRNA (Dab2 siRNA vs control siRNA: 71±18% for control cells; 83±29% for ARH cells).
“Similar results were obtained when the amount of LDL-receptor mRNA was expressed relative to 18S rRNA (Dab2 siRNA versus control siRNA: 71 + 18% for control cells; 83 + 29% for ARH cells).”
Quote in the paperNot a substantial claim - Findingown data
These inhibitors were able to inhibit the degradation of mutant forms of the LDL receptor that become trapped in the ER.
“In marked contrast, we showed that these inhibitors were able to inhibit the degradation of mutant forms of the LDL receptor that become trapped in the ER (Fig. 5B).”
Quote in the paperSubstantial claim - Interpretationown data
The slight reduction in Tf uptake in Dab2-depleted, LDLRAP1-deficient cells is probably due to a small reduction in Tf receptor protein in the cells.
“probably due to a small reduction in Tf receptor protein in the cells (Fig. 6).”
Quote in the paperNot a substantial claim - Interpretationown data
It seemed unlikely that the reduction of LDL receptor protein in Dab2-depleted ARH cells was due to off-target effects of the siRNA.
“Hence, it seemed unlikely that the reduction of LDL receptor protein in Dab2-depleted ARH cells was due to off-target effects of the siRNA.”
Quote in the paperSubstantial claim - Study design and conductown data
The efficiency of Dab2 depletion in the rescue experiment was at least 85%, as estimated from the number of cells with undetectable LDL-receptor protein.
“The efficiency of Dab2 depletion in this experiment was at least 85%, as estimated from the number of cells with undetectable LDL-receptor protein.”
Quote in the paperSubstantial claim - Study design and conductown data
These findings were confirmed in skin fibroblasts from two different control subjects and two unrelated ARH patients.
“These findings were confirmed in skin fibroblasts from two different control subjects and two unrelated ARH patients (Table 1).”
Quote in the paperSubstantial claim - Study design and conductown data
Non-saturable uptake of LDL by control cells was always <5% of total.
“Non-saturable uptake of LDL by control cells was always ,5% of total.”
Quote in the paperNot a substantial claim - Study design and conductown data
Dab2 expression was specifically and efficiently knocked down in both control and ARH fibroblasts with two different siRNA oligonucleotides targeted to different regions of Dab2.
“Dab2 expression was specifically and efficiently knocked down in both control fibroblasts (Fig. 1C) and ARH fibroblasts (Fig. 1D) with two different siRNA oligonucleotides targeted to different regions of Dab2 (siDab2-02 and -03).”
Quote in the paperSubstantial claim - Interpretationown data
LDLRAP1 is sufficient to promote endocytosis of the LDL receptor in fibroblasts in the absence of AP2.
“Our experiments are consistent with this, and indicate that LDLRAP1 is sufficient to promote endocytosis of the LDL receptor in fibroblasts in the absence of AP2.”
Quote in the paperSubstantial claim - Interpretationreasoning
Some component absent from skin fibroblasts must maintain LDL receptor protein integrity in HeLa cells and lymphocytes depleted of Dab2 and LDLRAP1.
“some component that is absent from skin fibroblasts must maintain LDL receptor protein integrity in HeLa cells and lymphocytes depleted of Dab2 and LDLRAP1.”
Quote in the paperSubstantial claim - Interpretationreasoning
The reduction in LDL-receptor protein is likely caused by reduced translation of LDL receptor mRNA.
“it is likely that it is caused by reduced translation of LDL receptor mRNA.”
Quote in the paperSubstantial claim - Study design and conductown data
Similar observations were made in fibroblasts from two different control subjects and two ARH patients.
“Similar observations were made in fibroblasts from two different control subjects and two ARH patients (Table 1).”
Quote in the paperNot a substantial claim - Interpretationreasoning
Functional redundancy may exist between LDLRAP1 and Dab2 in modulating LDL receptor synthesis.
“We propose that functional redundancy may exist between LDLRAP1 and Dab2 in modulating LDL receptor synthesis.”
Quote in the paperSubstantial claim - Premisecitation
LDLRAP1 is a cargo-specific adaptor required for clathrin-mediated endocytosis of the LDL receptor.
“Immortalized lymphocytes and monocyte-macrophages, and presumably hepatocytes, from ARH patients fail to take up and degrade plasma low density lipoproteins (LDL) because they lack LDLRAP1, a cargo-specific adaptor required for clathrinmediated endocytosis of the LDL receptor.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [3]
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- Interpretationown data
Combining these results with the very low amounts of newly synthesized LDL-receptor protein detected within 30 min strongly suggests that reduced translation is the likely cause for the diminished LDL-receptor observed in Dab2-depleted ARH cells.
“Combining these results with the very low amounts of newly synthesized LDL-receptor protein detected within 30 min (Fig. 4) strongly suggests that reduced translation is the likely cause for the diminished LDL-receptor we observed in Dab2-depleted ARH cells.”
- Also stated in: § Abstract · hedged
“Thus, we propose a novel role for Dab2 in ARH fibroblasts, where it is apparently required to allow normal translation of LDL receptor mRNA.”
Quote in the paperSubstantial claim - Also stated in: § Abstract · hedged
- Premisecitation
The Q136X mutation in LDLRAP1 results in undetectable levels of LDLRAP1 protein in cells.
“This mutation is known to result in undetectable levels of LDLRAP1 protein in cells (9).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [9]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationcitation
The component that maintains LDL receptor protein integrity in HeLa cells and lymphocytes depleted of Dab2 and LDLRAP1 is also present in the liver.
“Presumably, this component is also present in the liver, since Dab2 expression in whole liver has been reported to be very low (12) and has recently been shown to be absent from hepatocytes (18), and in arh 2 /2 mice lacking LDLRAP1, LDL-receptor protein also accumulates on the surface of hepatocytes in vivo (5).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [12]
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- Premisecitation
LDL-receptor protein is stable but trapped on the cell surface in lymphocytes and HeLa cells lacking ARH and Dab2.
“Quite why LDL-receptor protein is stable but trapped on the cell surface in the absence of ARH and Dab2 in lymphocytes and HeLa cells, but is unstable in ARH skin fibroblasts depleted of Dab2 is puzzling.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [4]
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- cites [17]
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- Interpretationreasoning
LDL-receptor protein trafficking differs in different cell types.
“Clearly, LDL-receptor protein trafficking differs in different cell types”
Quote in the paperSubstantial claim - Interpretationown data
The paper proposes a novel function for Dab2 in modulating LDL receptor protein synthesis in cells lacking LDLRAP1.
“Instead we propose a novel function for Dab2 in modulating LDL receptor protein synthesis in cells lacking LDLRAP1.”
Quote in the paperSubstantial claim - Interpretationown data
In the absence of LDLRAP1, AP2 may play some part in LDL-receptor internalization.
“This suggests that in the absence of LDLRAP1, AP2 may play some part in LDL-receptor internalization.”
Quote in the paperSubstantial claim - Premisecitation
LDL receptor protein accumulates on the surface of EBV-transformed lymphocytes from ARH patients.
“our earlier finding that LDLreceptor protein accumulates on the surface of EBVtransformed lymphocytes from ARH patients (4)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [4]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Study design and conductown data
These findings were confirmed in cells from two different control subjects and two ARH patients, using two different siRNA targeting Dab2.
“These findings were confirmed in cells from two different control subjects and two ARH patients, using two different siRNA targeting Dab2 (Fig. 6C).”
Quote in the paperSubstantial claim
- It may state two separate claims as one. 31
- Probably not a substantial claim. 18
- The quote only partly states this claim. 1
It may state two separate claims as one.
Findingown dataDab2 depletion results in reduction of LDLR protein in ARH fibroblasts but not in normal fibroblasts.
“we have demonstrated that Dab2 depletion results in the reduction of LDLR protein in ARH fibroblasts but not in normal fibroblasts.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataMean incorporation of 35S-labelled amino acids into mature LDL receptor protein in Dab2-depleted ARH cells was 45.2±18.9% of control siRNA after 4h chase and 33.5±14.7% after 8h chase; same values for control cells were 91.3±4.7 and 93.8±2.8%.
“Mean (+SD, n ¼ 3) incorporation of 35 S-labelled amino acids into mature LDL receptor protein in Dab2-depleted ARH cells was 45.2 + 18.9% of that in cells treated with control siRNA after 4 h chase and 33.5 + 14.7% after 8 h chase; the same values for control cells were 91.3 + 4.7 and 93.8 + 2.8%.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataLeupeptin was having some effect on protein degradation in these cells because Dab2 protein levels increased slightly in both control and ARH cells treated with control siRNA.
“Leupeptin was clearly having some effect on protein degradation in these cells because Dab2 protein levels increased slightly in both control and ARH cells treated with control siRNA (Fig. 5C, compare lanes 1 and 2; lanes 5 and 6).”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataDepletion of AP2-a in control fibroblasts did not affect LDL uptake, but in ARH fibroblasts it slightly reduced LDL uptake to 76±4% of that in cells transfected with a non-targeting siRNA.
“As shown by the open triangles in Figure 2A and B, LDL uptake was not affected by this partial depletion of AP2 in control fibroblasts, but in ARH fibroblasts, it was slightly reduced compared with that in cells transfected with a non-targeting siRNA (to 76 + 4%).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataDegradation of 125I-LDL reflected uptake in both control and ARH fibroblasts, showing that residual uptake by ARH cells was not due solely to binding to LDL receptors on the cell surface.
“Degradation of 125 I-LDL reflected uptake in both control (Fig. 2C) and ARH (Fig. 2D) fibroblasts, showing that residual uptake by ARH cells was not due solely to binding to LDL receptors on the cell surface.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataDab2 depletion had very little effect on Tf uptake in control cells, but in ARH cells, it was reduced to 64% of that in cells transfected with non-targeting siRNA.
“Dab2 depletion had very little effect on Tf uptake in control cells (Fig. 6A, closed triangles), but in ARH cells, it was reduced to 64% of that in cells transfected with a non-targeting siRNA (Fig. 6B, closed triangles).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataExpression of GFP did not restore LDL-receptor protein in any of 32 cells counted, but all GFP-Dab2-expressing cells also contained LDL receptor protein (28 cells counted).
“Expression of GFP did not restore LDL-receptor protein in any of 32 cells counted, but all GFP-Dab2-expressing cells also contained LDL receptor protein (28 cells counted).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataDab2 protein is highly expressed in cultured normal skin fibroblasts, whereas it is barely detectable in normal EBV-lymphocytes.
“Immunoblotting of whole cell extracts revealed high levels of Dab2 protein in cultured normal skin fibroblasts, whereas it was barely detectable in normal EBV-lymphocytes (Fig. 1A).”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataConfocal microscopy confirmed that siRNA depletion of Dab2 had no effect on LDL receptor protein in control cells, but had a profound effect in ARH cells.
“Confocal microscopy of cells stained with fluorescently labelled antibodies confirmed that while siRNA depletion of Dab2 had no effect on LDL receptor protein in control cells (data not shown), it had a profound effect in ARH cells.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Findingown dataA slight reduction in Tf receptor expression was observed in ARH cells depleted of Dab2.
“Interestingly, we also observed a slight reduction in Tf receptor expression in ARH cells depleted of Dab2 (Fig. 6); it is worth noting, however, that other proteins involved in trafficking were unaffected, for example, expression of two subunits of AP2 was unchanged by depletion of Dab2 (Fig. 1C and D).”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataDab2 knockdown resulted in significant reduction of LDL-receptor protein in ARH cells but not in control cells.
“Dab2 knockdown, however, resulted in significant reduction of LDL-receptor protein in ARH cells but not in control cells (Fig. 3A).”
- Also stated in: § Abstract · plain
“In contrast, LDL-receptor protein content was unchanged in Dab-2-depleted control cells.”
Quote in the paperSubstantial claim- Also stated in: § Abstract · plain
It may state two separate claims as one.
Findingown dataDepletion of Dab2 with two different siRNA in cells from two control subjects and two ARH patients with different mutations confirmed a decrease in LDL-receptor protein of up to 75% in ARH cells, but little or no change in cells from control subjects.
“Depletion of Dab2 with two different siRNA in cells from two control subjects and two ARH patients with different mutations confirmed a decrease in LDL-receptor protein of up to 75% in ARH cells, but little or no change in cells from control subjects (Fig. 3B).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
PremisecitationEBV-transformed lymphocytes from ARH patients fail to internalize the LDL receptor, while Tf-receptor mediated uptake and recycling of 125I-Tf occurs normally.
“Epstein -Barr virus (EBV)-transformed lymphocytes isolated from ARH patients fail to internalize the LDL receptor, while Tf-receptor mediated uptake and recycling of 125 I-Tf occurs normally, suggesting that the internalization defect does not affect all clathrin-mediated endocytosis, but rather is specific for the LDL receptor (3).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [3]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
It may state two separate claims as one.
Interpretationown dataEither LDL-receptor protein synthesis was reduced or newly synthesized protein was rapidly degraded.
“Thus, either LDL-receptor protein synthesis was reduced or newly synthesized protein was rapidly degraded.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Interpretationown dataTreatment of Dab2-depleted ARH cells with several different inhibitors of protein degradation had no effect on their LDL-receptor protein content, suggesting that rapid degradation of newly synthesized protein was also unlikely.
“However, we found that treatment of the Dab2-depleted ARH cells with several different inhibitors of protein degradation had no effect on their LDL-receptor protein content (Fig. 5A and C), suggesting that rapid degradation of newly synthesized protein was also unlikely.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Study design and conductown dataBoth Dab2 siRNAs were effective in reducing Dab2 protein under conditions that resulted in 85-95% transfection efficiency, but a more complete knockdown was achieved using siDab2-02.
“Both Dab2 siRNAs were effective in reducing Dab2 protein under conditions that resulted in 85 -95% transfection efficiency, but a more complete knockdown was achieved using siDab2-02.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
PremisecitationLDL-receptor internalization is severely disrupted in EBV-lymphocytes, monocyte macrophages, and presumably liver of ARH patients, but appears to occur normally in patients' skin fibroblasts in culture.
“A puzzling feature of LDLRAP1 is that while LDL-receptor internalization is severely disrupted in EBV-lymphocytes (3,9), monocyte macrophages (4) and, presumably, liver of ARH patients, it appears to occur normally in patients' skin fibroblasts in culture (4,10,11).”
Quote in the paperSubstantial claim0 of 5 sources checked- cites [3]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [9]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [4]
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- cites [10]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [11]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
It may state two separate claims as one.
PremisecitationDab2 binds the NPVY motif found in the LDL receptor, interacts directly with phosphoinositides, and binds both clathrin triskelia and the a-adaptin subunit of AP2.
“Disabled-2 (Dab2) is an alternative PTB domain-containing protein that, like LDLRAP1, binds the NPVY motif found in the LDL receptor, interacts directly with phosphoinositides (12) and binds both clathrin triskelia and the a-adaptin subunit of AP2 (13).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [12]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [13]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. It may state two separate claims as one.
PremisereasoningLDLRAP1 demonstrates all the features of a cargo-specific adaptor protein and is now widely viewed as an LDL receptor-specific endocytic adaptor protein.
“Thus, LDLRAP1 demonstrates all the features of a cargo-specific adaptor protein and is now widely viewed as an LDL receptor-specific endocytic adaptor protein.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenAll samples and standards were assayed in triplicate.
“All samples and standards were assayed in triplicate.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Interpretationown dataThe reduction in LDL receptor activity in Dab2-depleted cells resulted from the marked reduction in LDL-receptor protein content, but a similar reduction could not account for the 25% fall in activity in AP2-depleted cells.
“Thus the reduction in LDL receptor activity in Dab2-depleted cells resulted from the marked reduction in LDL-receptor protein content, but a similar reduction could not account for the 25% fall in activity in AP2-depleted cells.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Study design and conductown dataA non-targeting siRNA had no effect on Dab2 expression in control or ARH cells, and depletion of Dab2 had no effect on the expression of AP2-a or -m2.
“A non-targeting siRNA had no effect on Dab2 expression in control or ARH cells (Fig. 1C and D) and depletion of Dab2 had no effect on the expression of AP2-a or -m2.”
Quote in the paperNot a substantial claimProbably not a substantial claim. It may state two separate claims as one.
PremisecitationIn HeLa cells, simultaneous siRNA-mediated reduction of both LDLRAP1 and Dab-2 results in impaired LDL receptor mediated internalization of LDL and accumulation of LDL receptor protein at the cell surface.
“Recently, it has been shown that in HeLa cells, simultaneous siRNA-mediated reduction of both LDLRAP1 and Dab-2 results in impaired LDL receptor mediated internalization of LDL and accumulation of LDL receptor protein at the cell surface (17,18).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [17]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [18]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationA protective role has been proposed by others for Dab1, the neuronal counterpart and structural homologue of Dab2, which has been reported to chaperone VLDL receptor and ApoER2 to the cell surface.
“Such a protective role has been proposed by others for Dab1, the neuronal counterpart and structural homologue of Dab2, which has been reported to chaperone the very low density lipoprotein (VLDL) receptor and apolipoprotein E receptor 2 (ApoER2) to the cell surface (28).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [28]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationsiRNA targeting of m2 prevents uptake of 125I-Tf in HeLa cells.
“Indeed siRNA targeting of m2 has been shown by others to prevent uptake of 125 I-Tf in HeLa cells (24,25).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [24]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [25]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductown dataThe data shown in Figure 2 are the mean of three separate experiments plus SEM.
“the data shown are the mean of three separate experiments +SEM.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenFor each experiment, cells from one well of a six-well plate were assayed for knockdown efficiency by immunoblotting of whole cell extracts with appropriate antibodies.
“For each experiment, cells from one well of a six-well plate were assayed for knockdown efficiency by immunoblotting of whole cell extracts with appropriate antibodies.”
Quote in the paperNot a substantial claimProbably not a substantial claim.
Study design and conductown dataSaturable uptake and degradation of LDL was determined in duplicate dishes.
“Saturable uptake (A and B) and degradation (C and D) of LDL was determined in duplicate dishes”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Study design and conductown dataThe overall rate of incorporation of radioactivity into total cell protein was not different between control and ARH cells and was not affected by Dab2-depletion.
“The overall rate of incorporation of radioactivity into total cell protein was not different between the control and ARH cells and was not affected by Dab2-depletion (data not shown).”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationDepletion of AP2 with siRNA directed to m2-subunit has been shown by others to reduce markedly uptake of Tf by HeLa cells.
“Depletion of AP2 with siRNA directed to the m2-subunit has been shown by others to reduce markedly the uptake of Tf by HeLa cells (24,25).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [24]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [25]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductown dataThe data shown in Figure 6 are the mean of duplicate values in three separate experiments.
“Data shown are the mean of duplicate values in three separate experiments.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Interpretationown dataEfficient knockdown of Dab2 severely disrupted LDL uptake in ARH fibroblasts that lack LDLRAP1, but since this was accompanied by a corresponding reduction in LDL receptor protein, the role of Dab2 in clathrin-mediated endocytosis of the LDL receptor in skin fibroblasts remains unresolved.
“Efficient knockdown of Dab2 (Fig. 1) severely disrupted LDL uptake in ARH fibroblasts that lack LDLRAP1 (Fig. 2), but since this was accompanied by a corresponding reduction in LDL receptor protein (Fig. 3), the role of Dab2 in clathrin-mediated endocytosis of the LDL receptor in skin fibroblasts remains unresolved.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
PremisecitationLDLRAP1-deficient mice develop hypercholesterolaemia and exhibit defective internalization of LDL receptors in their hepatocytes in vivo.
“Moreover, LDLRAP1deficient mice develop hyper-cholesterolaemia and exhibit defective internalization of LDL receptors in their hepatocytes in vivo (5).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [5]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationIn HeLa cells, depletion of LDLRAP1 and AP2 had no measurable effect on LDL-receptor internalization as long as Dab2 was present.
“others have found that depletion of LDLRAP1 and AP2 apparently had no measurable effect on LDL-receptor internalization in these cells as long as Dab2 was present (17,18).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [17]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [18]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenTransfection efficiency was optimized using siGLO.
“Transfection efficiency was optimized using siGLO (RISC-Free siRNA).”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenConditions for transfection were optimized with fluorescently labelled siRNA.
“Conditions for transfection were optimized with fluorescently labelled siRNA (data not shown).”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
PremisecitationIn HeLa cells, simultaneous depletion of Dab2 and LDLRAP1 with siRNA resulted in decreased uptake of fluorescently labelled LDL and accumulation of LDL-receptor protein on the cell surface.
“In these cells, simultaneous depletion of Dab2 and LDLRAP1 with siRNA resulted in decreased uptake of fluorescently labelled LDL and accumulation of LDL-receptor protein on the cell surface (17,18).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [17]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [18]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
It may state two separate claims as one.
Study design and conductown dataIt was not possible to determine whether the proportion of precursor converted to mature receptor was affected because radioactivity in precursor bands was insufficient to permit accurate quantification in Dab2-depleted ARH cells and no accumulation of precursor protein was evident on autoradiographs.
“It was not possible to determine whether the proportion of precursor converted to mature receptor was affected because the radioactivity in precursor bands was insufficient to permit accurate quantification in Dab2-depleted ARH cells and no accumulation of precursor protein was evident on autoradiographs (Fig. 4B, lower panel).”
Quote in the paperNot a substantial claimProbably not a substantial claim.
PremisecitationMutations in the AP2 binding site of LDLRAP1 did not prevent LDLRAP1-mediated clustering of LDL receptor in clathrin-coated pits unless the binding sites for clathrin were also disrupted.
“Others have observed that mutations in the AP2 binding site of LDLRAP1 did not prevent LDLRAP1mediated clustering of LDL receptor in clathrin-coated pits unless the binding sites for clathrin were also disrupted (32).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [32]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
It may state two separate claims as one.
PremisecitationAlthough uptake of both Tf and LDL receptors is dependent on clathrin-mediated endocytosis, the internalization of these cargos involves distinct mechanisms.
“there is a body of evidence to suggest that although uptake of both Tf and LDL receptors is dependent on clathrin-mediated endocytosis, the internalization of these cargos involves distinct mechanisms (3,24,30,31).”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [3]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [24]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [30]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [31]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The quote only partly states this claim.
Study design and conductown dataThe data shown in Figure 3B are the mean of three separate experiments plus SEM.
“The data shown are the mean of three separate experiments +SEM.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationDab2 has been implicated as an endocytic adaptor for other members of the LDL-receptor family such as apoER2 and megalin.
“Moreover, Dab2 has been implicated as an endocytic adaptor for other members of the LDL-receptor family such as the apolipoprotein E receptor 2 (apoER2) (14) and megalin (15,16).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [14]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [15]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [16]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
It may state two separate claims as one.
PremisecitationRetroviral expression of wild-type human LDLRAP1 in an EBV-lymphocyte cell line from an ARH patient restored LDL-receptor internalization, confirming that LDLRAP1 is required specifically for clathrin-mediated endocytosis of the LDL receptor in these cells.
“Retroviral expression of wild-type human LDLRAP1 in an EBV-lymphocyte cell line from an ARH patient restored LDL-receptor internalization, confirming that LDLRAP1 is # 2007 The Author(s) required specifically for clathrin-mediated endocytosis of the LDL receptor in these cells (4).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [4]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
It may state two separate claims as one.
Interpretationown dataQuantitative real-time RT-PCR found no associated change in LDLR mRNA in Dab2-depleted ARH cells; the reduction in LDL receptor protein is therefore likely to be the result of increased degradation or reduced translation rather than decreased transcription.
“In addition, we found by quantitative real-time RT -PCR that there was no associated change in LDLR mRNA in Dab2-depleted ARH cells; the reduction in LDL receptor protein is therefore likely to be the result of increased degradation or reduced translation rather than decreased transcription.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationThe LDL receptor is synthesized in the ER as a precursor with an apparent molecular mass of 120 KDa; within 30 min, it is transported to the Golgi complex where post-translational modifications result in the production of mature protein with increased apparent molecular mass (160 KDa).
“The LDL receptor is synthesized in the endoplasmic reticulum (ER) as a precursor with an apparent molecular mass of 120 KDa.Within 30 min, it is transported to the Golgi complex where post-translational modifications result in the production of mature protein with increased apparent molecular mass (160 KDa) (27).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [27]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
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?
Expression of Dab2 in polarized epithelial cells in developing circumventricular organs may be consistent with the functions of Dab2 in mediating endocytic trafficking of clathrin-coated vesicles and in directing cell surface positioning.
“Expression of Dab2 in polarized epithelial cells in developing circumventricular organs may be consistent with the well-documented functions of Dab2 in mediating endocytic trafficking of clathrin-coated vesicles [58,59], and in directing cell surface positioning [60].”
From Dynamic expression of Dab2 in the mouse embryonic central nervous system (2008) · cites this paper as [58]
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.
Conflicting LPDS incubation times for LDL uptake assay
MajorThe Figure 2 caption says cells spent a further 40 hours in LPDS-containing medium before the LDL assay, whereas the methods specify 16-18 hours for LDL uptake and degradation measurements.
“After 48 h, cells were transferred to medium containing LPDS for a further 40 h and then incubated for 4 h at 378C with 125 I-labelled LDL at the indicated concentrations.”
“For measurement of LDL-receptor protein or mRNA, or uptake or degradation of 125 I-labelled LDL, cells were then incubated for 16 -18 h in medium supplemented with 10% (v/v) LPDS.”
Figure 6 gives a different denominator for Tf uptake
MinorThe Figure 6 caption says uptake was expressed as a percentage of counts in the lysate, but the assay methods say intracellular counts were expressed as a percentage of total counts recovered across the medium, acid wash and lysate.
“the internalization and recycling of 125 I-labelled Tf was determined and expressed as a percentage of the total counts in the lysate.”
“Radioactivity in the medium (recycled 125 I-labelled Tf), acid wash (surface-bound) and the cell lysate (intracellular) was quantified and the intracellular component was expressed as a percentage of total counts recovered at each time point.”
Citations
Cites
Clathrin-mediated endocytosis in AP-2–depleted cells
Motley, A. M., Bright, N. A., Seaman, M. N. J., & Robinson, M. S. (2003) · The Journal of Cell Biology · doi:10.1083/jcb.200305145 · Cited by 709
Hopkins, C. R., & Trowbridge, I. S. (1983) · The Journal of Cell Biology · doi:10.1083/jcb.97.2.508 · Cited by 637
Garcia, C. K., Wilund, K., Arca, M., Zuliani, G., Fellin, R., Maioli, M., Calandra, S., Bertolini, S., Cossu, F., Grishin, N., et al. (2001) · Science · doi:10.1126/science.1060458 · Cited by 624
Hirst, J., & Robinson, M. S. (1998) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/s0167-4889(98)00056-1 · Cited by 389
Biosynthesis of N- and O-linked oligosaccharides of the low density lipoprotein receptor.
Cummings, R. D., Kornfeld, S. A., Schneider, W. J., Hobgood, K. K., Tolleshaug, H., Brown, M. S., & Goldstein, J. L. (1983) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)43802-6 · Cited by 366
Tofaris, G. K., Layfield, R., & Spillantini, M. G. (2001) · FEBS Letters · doi:10.1016/s0014-5793(01)03115-5 · Cited by 363
Disabled‐2 exhibits the properties of a cargo‐selective endocytic clathrin adaptor
Mishra, S. K., Keyel, P. A., Hawryluk, M. J., Agostinelli, N. R., Watkins, S. C., & Traub, L. M. (2002) · The EMBO Journal · doi:10.1093/emboj/cdf487 · Cited by 302
Hinrichsen, L., Harborth, J., Andrees, L., Weber, K., & Ungewickell, E. J. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m307290200 · Cited by 238
ARH Is a Modular Adaptor Protein That Interacts with the LDL Receptor, Clathrin, and AP-2
He, G., Gupta, S., Yi, M., Michaely, P., Hobbs, H. H., & Cohen, J. C. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m208539200 · Cited by 232
Disabled‐2 Colocalizes with the LDLR in Clathrin‐Coated Pits and Interacts with AP‐2
Morris, S. M., & Cooper, J. A. (2001) · Traffic · doi:10.1034/j.1600-0854.2001.020206.x · Cited by 222
Common principles in clathrin-mediated sorting at the Golgi and the plasma membrane
Traub, L. M. (2005) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2005.04.005 · Cited by 208
Differential requirements for AP-2 in clathrin-mediated endocytosis
Conner, S. D., & Schmid, S. L. (2003) · The Journal of Cell Biology · doi:10.1083/jcb.200304069 · Cited by 196
The adaptor protein Dab2 sorts LDL receptors into coated pits independently of AP-2 and ARH
Maurer, M. E., & Cooper, J. A. (2006) · Journal of Cell Science · doi:10.1242/jcs.03217 · Cited by 195
Tolleshaug, H., Goldstein, J. L., Schneider, W. J., & Brown, M. S. (1982) · Cell · doi:10.1016/0092-8674(82)90276-8 · Cited by 186
Dual roles for the Dab2 adaptor protein in embryonic development and kidney transport
Morris, S. M., Tallquist, M. D., Rock, C. O., & Cooper, J. A. (2002) · The EMBO Journal · doi:10.1093/emboj/21.7.1555 · Cited by 186
Kingsley, D. M., & Krieger, M. (1984) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.81.17.5454 · Cited by 180
Mishra, S. K., Watkins, S. C., & Traub, L. M. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.252630799 · Cited by 155
Keyel, P. A., Mishra, S. K., Roth, R., Heuser, J. E., Watkins, S. C., & Traub, L. M. (2006) · Molecular Biology of the Cell · doi:10.1091/mbc.e06-05-0421 · Cited by 134
Molecular mechanisms of autosomal recessive hypercholesterolemia
Wilund, K. R. (2002) · Human Molecular Genetics · doi:10.1093/hmg/11.24.3019 · Cited by 113
Endocytosis of megalin by visceral endoderm cells requires the Dab2 adaptor protein
Maurer, M. E., & Cooper, J. A. (2005) · Journal of Cell Science · doi:10.1242/jcs.02650 · Cited by 106
Distinct saturable pathways for the endocytosis of different tyrosine motifs
Warren, R. A., Green, F. A., Stenberg, P. E., & Enns, C. A. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.27.17056 · Cited by 103
Genetics, Clinical Phenotype, and Molecular Cell Biology of Autosomal Recessive Hypercholesterolemia
Soutar, A. K., Naoumova, R. P., & Traub, L. M. (2003) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/01.atv.0000094410.66558.9a · Cited by 99
Self-citationGaruti, R., Jones, C., Li, W.-P., Michaely, P., Herz, J., Gerard, R. D., Cohen, J. C., & Hobbs, H. H. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m509394200 · Cited by 91
Disabled1 Regulates the Intracellular Trafficking of Reelin Receptors
Morimura, T., Hattori, M., Ogawa, M., & Mikoshiba, K. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m409048200 · Cited by 81
Jones, C., Hammer, R. E., Li, W.-P., Cohen, J. C., Hobbs, H. H., & Herz, J. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m304855200 · Cited by 80
Eden, E. R., Patel, D., Sun, X.-M., Burden, J. J., Themis, M., Edwards, M., Lee, P., Neuwirth, C. K. Y., Naoumova, R. P., & Soutar, A. K. (2002) · Journal of Clinical Investigation · doi:10.1172/jci16445 · Cited by 76
Self-citationCuitino, L., Matute, R., Retamal, C., Bu, G., Inestrosa, N. C., & Marzolo, M. (2005) · Traffic · doi:10.1111/j.1600-0854.2005.00320.x · Cited by 72
Norman, D., Sun, X.-M., Bourbon, M., Knight, B. L., Naoumova, R. P., & Soutar, A. K. (1999) · Journal of Clinical Investigation · doi:10.1172/jci6677 · Cited by 69
Self-citationEden, E. R., Patel, D. D., Sun, X.-M., Burden, J. J., Themis, M., Edwards, M., Lee, P., Neuwirth, C., Naoumova, R. P., & Soutar, A. K. (2002) · Journal of Clinical Investigation · doi:10.1172/jci0216445 · Cited by 64
Self-citationSun, X.-M., Patel, D. D., Knight, B. L., & Soutar, A. K. (1997) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.17.11.3092 · Cited by 59
Self-citationSevere hypercholesterolaemia: unusual inheritance in an Italian pedigree
ZULIANI, G., VIGNA, G. B., CORSINI, A., MAIOLI., M., ROMAGNONI, F., & FELLIN, R. (1995) · European Journal of Clinical Investigation · doi:10.1111/j.1365-2362.1995.tb01709.x · Cited by 44
Degradation of the LDL receptor class 2 mutants is mediated by a proteasome-dependent pathway
Li, Y., Lü, W., Schwartz, A. L., & Bu, G. (2004) · Journal of Lipid Research · doi:10.1194/jlr.m300482-jlr200 · Cited by 33
Expression of an LDL receptor allele with two different mutations (E256K and I402T)
Ekström, U. (2000) · Molecular Pathology · doi:10.1136/mp.53.1.31 · Cited by 20
Lactacystin Increases LDL Receptor Level on HepG2 Cells
Miura, H., Tomoda, H., Miura, K., Takishima, K., & Ōmura, S. (1996) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1996.1569 · Cited by 17
Knight, B. L., Patel, D. D., & Soutar, A. K. (1987) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1987.tb10754.x · Cited by 16
Self-citationAn individual with a healthy phenotype in spite of a pathogenic LDL receptor mutation (C240F)
Ekström, U., Abrahamson, M., Florén, C., Tollig, H., Wettrell, G., Nilsson, G., Sun, X., Soutar, A. K., & Nilsson‐Ehle, P. (1999) · Clinical Genetics · doi:10.1034/j.1399-0004.1999.550506.x · Cited by 6
Self-citation
Flagged first, then by citations
Research works printed but not linked: 1
- Bonifacino, J.S. (1998) TCA precipitation to determine label incorporation (unit 10.18.7). In Ausubel, F.M., Brent, R., Kingston, R.E., Moore, D.D., Seidman, J.G., Smith, J.A. and Struhl, K. (eds), Current Protocols in Molecular Biology. John Wiley & Sons, NY, Vol. 2.
Cited by
Sorted by citations
Tickets to ride: selecting cargo for clathrin-regulated internalization
Traub, L. M. (2009) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2751 · Cited by 597
Cargo- and adaptor-specific mechanisms regulate clathrin-mediated endocytosis
Mettlen, M., Loerke, D., Yarar, D., Danuser, G., & Schmid, S. L. (2010) · Journal of Cell Biology · doi:10.1083/jcb.200908078 · Cited by 177
Sorrentino, V., Nelson, J. K., Maspero, E., Marques, A. R. A., Scheer, L., Polo, S., & Zelcer, N. (2013) · Journal of Lipid Research · doi:10.1194/jlr.m037713 · Cited by 68
AMN Directs Endocytosis of the Intrinsic Factor-Vitamin B12 Receptor Cubam by Engaging ARH or Dab2
Pedersen, G. A., Chakraborty, S., Steinhauser, A. L., Traub, L. M., & Madsen, M. M. (2010) · Traffic · doi:10.1111/j.1600-0854.2010.01042.x · Cited by 67
Clathrin Regulates the Association of PIPKIγ661 with the AP-2 Adaptor β2 Appendage
Thieman, J. R., Mishra, S., Ling, K., Doray, B., Anderson, R. A., & Traub, L. M. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m901017200 · Cited by 53
The AP-2 Adaptor β2 Appendage Scaffolds Alternate Cargo Endocytosis
Keyel, P. A., Thieman, J. R., Roth, R. A., Erkan, E., Everett, E. T., Watkins, S. C., Heuser, J. E., & Traub, L. M. (2008) · Molecular Biology of the Cell · doi:10.1091/mbc.e08-07-0712 · Cited by 52
Tamborindeguy, C., Monsion, B., Brault, V., Hunnicutt, L. E., Ju, H.-J., Nakabachi, A., & Fleet, E. V. (2010) · Insect Molecular Biology · doi:10.1111/j.1365-2583.2009.00956.x · Cited by 35
Rare genetic causes of autosomal dominant or recessive hypercholesterolaemia
Soutar, A. K. (2010) · IUBMB Life · doi:10.1002/iub.299 · Cited by 27
Self-citationFiligheddu, F., Quagliarini, F., Campagna, F., Secci, T., Degortes, S., Zaninello, R., Argiolas, G., Verna, R., Pitzoi, S., Frau, F., et al. (2009) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2009.04.027 · Cited by 27
Soufi, M., Rust, S., Walter, M., & Schaefer, J. R. (2013) · Gene · doi:10.1016/j.gene.2013.03.034 · Cited by 25
Tada, H., Kawashiri, M., Nohara, A., Inazu, A., Kobayashi, J., Mabuchi, H., & Yamagishi, M. (2014) · Journal of Atherosclerosis and Thrombosis · doi:10.5551/jat.27227 · Cited by 25
Dynamic expression of Dab2 in the mouse embryonic central nervous system
Cheung, K.-K., Mok, S. C., Rezaie, P., & Chan, W. Y. (2008) · BMC Developmental Biology · doi:10.1186/1471-213x-8-76 · Cited by 23
Pal, R., Ke, Q., Pihan, G. A., Yesilaltay, A., Penman, M., Wang, L., Chitraju, C., Kang, P. M., Krieger, M., & Kocher, O. N. (2016) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00463.2016 · Cited by 23
Endocytic Adaptors in Cardiovascular Disease
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Jha, A., Watkins, S. C., & Traub, L. M. (2012) · Molecular Biology of the Cell · doi:10.1091/mbc.e11-11-0939 · Cited by 21
Sorkin, A. D., & Puthenveedu, M. A. (2013) · Springer eBooks · doi:10.1007/978-1-4614-6528-7_1 · Cited by 21
Modulation of PICALM Levels Perturbs Cellular Cholesterol Homeostasis
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Self-citationHarders, R. H., Morthorst, T. H., Landgrebe, L. E., Lande, A. D., Fuglsang, M., Mortensen, S. B., Feteira-Montero, V., Jensen, H. H., Wesseltoft, J. B., & Olsen, A. (2024) · G3 Genes Genomes Genetics · doi:10.1093/g3journal/jkae088 · Cited by 3
Regulation of the LDL receptor in familial hypercholesterolemia
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Endocytosis of Cargo Proteins: LDL
Traub, L. M. (2015) · Elsevier eBooks · doi:10.1016/b978-0-12-394447-4.30024-4 · Cited by 1
Genetic Disorders of the Lipoprotein Metabolism; Diagnosis and Management
Bakker, A. C., Jakulj, L., & Kastelein, J. J. P. (2010) · Springer eBooks · doi:10.1007/978-1-84996-471-5_20 · Cited by 1
Regulation of clathrin-coated vesicle nucleation
Thieman, J. R. (2011) · D-Scholarship@Pitt (University of Pittsburgh)
Genetic Disorders of Lipoprotein Metabolism: Diagnosis and Management
Cupido, A. J., Stoekenbroek, R. M., & Kastelein, J. J. P. (2020) · Springer eBooks · doi:10.1007/978-3-030-45457-9_23
Influence of Genome-wide Variation on Complex Disease Risk in 22q11.2 Deletion Syndrome
Ying, S. J. (2022) · TSpace (University of Toronto)
Metadata
- Authors
- Eden, E. R., Sun, X.-M., Patel, D. D., & Soutar, A. K.
- Affiliations
- Hammersmith Hospital (GB)
- Corresponding author
- Soutar, A. K.
- ORCID
- Eden, E. R.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2007-06-27
- Volume
- 16
- Issue
- 22
- Pages
- 2751-2759
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2154736856
- Semantic Scholar
- 6ee1d2ee657b0a817b86c0963855f1d450971a00
- Cited by
- 27
- References
- 36
- Citations by year
- 2024: 1 · 2022: 1 · 2020: 2 · 2019: 1 · 2016: 2 · 2015: 2 · 2014: 1 · 2013: 3 · 2012: 1
- FWCI
- 1.45
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Human Molecular Genetics (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- British Heart Foundation
- Medical Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- Disabled-2, LDLRAP1, LDL receptor, clathrin-mediated endocytosis, dermal fibroblasts, mRNA translation, siRNA knockdown
- MeSH terms
- Animals, Cricetulus, Endocytosis, Fibroblasts, Genes, Recessive, Cricetinae, Humans, Hyperlipoproteinemia Type II, Lymphocytes, Receptors, LDL, RNA, Messenger, Skin, Transcription, Genetic, Case-Control Studies, CHO Cells, Adaptor Protein Complex 2, RNA, Small Interfering, Adaptor Proteins, Signal Transducing
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