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SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis
Open accessAbstract
A non-synonymous single nucleotide polymorphism in the human SLC24A5 gene is associated with natural human skin color variation. Multiple sequence alignments predict that this gene encodes a member of the potassium-dependent sodium-calcium exchanger family denoted NCKX5. In cultured human epidermal melanocytes we show using affinity-purified antisera that native human NCKX5 runs as a triplet of approximately 43 kDa on SDS-PAGE and is partially localized to the trans-Golgi network. Removal of the NCKX5 protein through small interfering RNA-mediated knockdown disrupts melanogenesis in human and murine melanocytes, causing a significant reduction in melanin pigment production. Using a heterologous expression system, we confirm for the first time that NCKX5 possesses the predicted exchanger activity. Site-directed mutagenesis of NCKX5 and NCKX2 in this system reveals that the non-synonymous single nucleotide polymorphism in SLC24A5 alters a residue that is important for NCKX5 and NCKX2 activity. We suggest that NCKX5 directly regulates human epidermal melanogenesis and natural skin color through its intracellular potassium-dependent exchanger activity.
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TL;DR
SLC24A5 encodes NCKX5, a potassium-dependent sodium-calcium exchanger that is partially localized to the trans-Golgi network in human epidermal melanocytes and is required for melanin synthesis. The skin-color-associated nsSNP rs1426654 changes a conserved residue and reduces NCKX5/NCKX2 exchange activity.
Key findings
- SLC24A5 was the predominant sodium-calcium exchanger transcript in cultured human and mouse melanocytes, >100-fold more highly expressed than any other SLC24A transcript; SLC8 family transcripts were not detected.
- Native NCKX5 ran as a ~43-kDa triplet on SDS-PAGE, partially co-localized with the trans-Golgi marker TGN46, showed no plasma membrane staining, and co-fractionated with TGN46 and pigment/TYRP1-enriched fractions.
- SLC24A5 knockdown reduced melanin production: 87.7% in mouse B16 melanocytes (p < 0.0001), 22% and 30.5% in NHM with siRNA 185 and 492 (p < 0.0001), and 80–90% in re-differentiating melanoblasts (p < 0.0001); melanosomal markers pmel17, MART1, TYR, and TYRP1 were reduced, while LAMP-1 increased.
- NCKX5 showed K+-dependent Na+/Ca2+ exchange activity, and the threonine-encoding allele at NCKX5 residue 111 or the equivalent NCKX2 residue 177 caused substantially reduced exchanger activity.
Methods
- Cultured normal human melanocytes (NHM), B16 F10 mouse melanoma cells, HEK293 cells, and High Five insect cells were used with real-time PCR, immunoblotting, immunofluorescence confocal microscopy, sucrose density gradient fractionation, and melanin assays.
- SLC24A5 was knocked down with siRNA duplexes in B16 and NHM, including de-differentiated melanoblasts; melanin was normalized to protein and analyzed by ANOVA with Dunnett’s adjustment.
- NCKX2 and NCKX5 mutants were expressed in High Five cells, and reverse exchange was measured as K+-dependent 45Ca2+ uptake in Na+-loaded cells.
Limitations
- The paper states that the unique intracellular localization of NCKX5 necessitated new assays because current methodologies were not suitable for measuring intracellular sodium-calcium exchange activity, and NCKX5 activity in the heterologous system was low.
- The paper states that it cannot rule out a cryptic melanosomal localization for NCKX5, that the identity of the punctate staining was not determined, and that no co-localization between NCKX5 and melanosomal markers was detected by immunofluorescence.
- Evident from the text: the NHM total-melanin knockdown effect was modest (22–30.5%), and the anti-NCKX5 antisera showed some nonspecific reactivity on Western blots.
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35 Own result · 26 Not checked yet · 18 Own interpretation · 4 Own method · 3 No basis given · 2 Supported
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In the paper
“Using data from the human HapMap project (8), they observed that the alternate alleles of the nsSNP (rs1426654) in human SLC24A5 were present at very different frequencies in populations of African and European ancestry.”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > Abstract
What the sources say
- Supportedcites [8] Consortium, 2005, Nature source
The citation identifies the human HapMap project as the source of the data, and this paper reports its Phase I data. Table 9 lists rs1426654 in SLC24A5 among high-differentiation non-synonymous SNPs; the Phase I HapMap section identifies the Yoruba (YRI) and Utah (CEU) sample panels. (LLM, conf=0.88)
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In the paper
“In cultured human epidermal melanocytes we show using affinity-purified antisera that native human NCKX5 runs as a triplet of ϳ43 kDa on SDS-PAGE and is partially localized to the trans-Golgi network.”
- Also stated in: § NCKX5 Protein Is Located in an Intracellular · boosted
“Western blots of cell extracts harvested 5 days after transfection and probed with affinity-purified anti-NCKX5-(C) sera showed that a triplet of bands of ϳ43 kDa were clearly detected in extracts from control or untreated cells but were virtually absent in extracts from SLC24A5 siRNA-treated cells (Fig. 2A).”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > Abstract
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- Also stated in: § NCKX5 Protein Is Located in an Intracellular · boosted
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In the paper
“In cultured human epidermal melanocytes we show using affinity-purified antisera that native human NCKX5 runs as a triplet of ϳ43 kDa on SDS-PAGE and is partially localized to the trans-Golgi network.”
- Also stated in: § NCKX5 Protein Is Located in an Intracellular · plain
“The perinuclear staining colocalized with the trans-Golgi marker TGN46 (Fig. 2C), although merged images of serial optical sections revealed that NCKX5 only co-localized with part of the TGN (Fig. 3A).”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > Abstract
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- Also stated in: § NCKX5 Protein Is Located in an Intracellular · plain
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In the paper
“Site-directed mutagenesis of NCKX5 and NCKX2 in this system reveals that the non-synonymous single nucleotide polymorphism in SLC24A5 alters a residue that is important for NCKX5 and NCKX2 activity.”
- Also stated in: § SLC24A5 Knockdown Reduces Melanin Production in NHM- · plain
“Constructs carrying the threonine variant had a greatly reduced exchange activity compared with those carrying the alanine variant (Fig. 8C).”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > Abstract
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- Also stated in: § SLC24A5 Knockdown Reduces Melanin Production in NHM- · plain
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In the paper
“Using a heterologous expression system, we confirm for the first time that NCKX5 possesses the predicted exchanger activity.”
- Also stated in: § SLC24A5 Knockdown Reduces Melanin Production in NHM- · boosted
“Reverse exchange of NCKX5 was only observed when extracellular K ϩ was present and no reverse exchange was observed in the presence of either extracellular Na ϩ or Li ϩ , confirming K ϩ -dependent Na ϩ /Ca 2ϩ exchange function.”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > Abstract
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- Also stated in: § SLC24A5 Knockdown Reduces Melanin Production in NHM- · boosted
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
“Removal of the NCKX5 protein through small interfering RNAmediated knockdown disrupts melanogenesis in human and murine melanocytes, causing a significant reduction in melanin pigment production.”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > Abstract
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In the paper
“SLC24A5 knockdown with two different siRNA duplexes in cultured NHM reproducibly results in greater than a 20% reduction in the total normalized melanin content of these cells (Fig. 6A).”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > DISCUSSION
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“SLC24A5 mRNA Is the Predominant Sodium-Calcium Exchanger Transcript in Human and Mouse Melanocytes-In mammalian cells sodium-calcium exchange is mediated both”
- Also stated in: § SLC24A5 mRNA Is the Predominant Sodium-Calcium Exchanger Transcript in Human and Mouse Melanocytes-In mammalian cells sodium-calcium exchange is mediated both · plain
“In both cultures the predominant isoform was SLC24A5, which was Ͼ100fold more highly expressed than any of the other SLC24A transcripts, and transcripts of the SLC8 family were not detected in either cell line.”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > SLC24A5 mRNA Is the Predominant Sodium-Calcium Exchanger Transcript in Human and Mouse Melanocytes-In mammalian cells sodium-calcium exchange is mediated both
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- Also stated in: § SLC24A5 mRNA Is the Predominant Sodium-Calcium Exchanger Transcript in Human and Mouse Melanocytes-In mammalian cells sodium-calcium exchange is mediated both · 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
“In both cultures the predominant isoform was SLC24A5, which was Ͼ100fold more highly expressed than any of the other SLC24A transcripts, and transcripts of the SLC8 family were not detected in either cell line.”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > SLC24A5 mRNA Is the Predominant Sodium-Calcium Exchanger Transcript in Human and Mouse Melanocytes-In mammalian cells sodium-calcium exchange is mediated both
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In the paper
“However no marked effect on the punctate staining was observed (Fig. 3C).”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > NCKX5 Protein Is Located in an Intracellular
plain- Asserted: passes — The authors put it forward as true.
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“NCKX5 Co-fractionates with TGN46 in NHM Extracts-Subcellular fractionation provides an alternative approach to determine the localization of proteins.”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > NCKX5 Protein Is Located in an Intracellular
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In the paper
“Treatment with siRNA 762 elicited a marked and reproducible reduction in melanin production 72 h postknockdown (87.7% reduction p Ͻ 0.0001) compared with the control siRNA (Fig. 5, A and B) without any detectable toxicity.”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > SLC24A5 Knockdown Reduces Melanin Production in Mouse B16
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In the paper
“Conversely, expression of the lysosomal marker LAMP-1 was up-regulated after SLC24A5 knockdown, suggesting that SLC24A5 plays a role very early in melanosome biogenesis and that this process is intimately linked with lysosome biogenesis.”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > SLC24A5 Knockdown Reduces Melanin Production in NHM-
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In the paper
“Costaining of NHM with anti-NCKX5 and the cis-Golgi marker GM130 (Fig. 3B) showed that the location of the two antigens was close though not coincident with a separation of ϳ300 -500 nm, calculated from plots of signal intensity in each channel across multiple sections the Golgi stacks.”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > NCKX5 Protein Is Located in an Intracellular
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“NHM transfected with either of the SLC24A5 knockdown siRNAs (Fig. 6A) resulted in significant percentage reductions of 22 and 30.5% (siRNA 185 and 492, respectively; p Ͻ 0.0001) of total cellular melanin compared with the control cells, demonstrating that SLC24A5 expression plays an important role in melanin synthesis in these cells.”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > SLC24A5 Knockdown Reduces Melanin Production in NHM-
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“The residue altered by the nsSNP in SLC24A5 lies in a region of the protein that is highly conserved across all NCKX family members.”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > Abstract
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“Transfection of de-differentiated cells with SLC24A5 siRNA knockdown duplexes (185 and 492) almost completely blocked pigment synthesis after switching back into melanocyte media compared with the control transfection (Fig. 6B, SC) with a normalized percentage difference in melanin content of 80 -90% (p Ͻ 0.0001).”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > SLC24A5 Knockdown Reduces Melanin Production in NHM-
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“Colocalization studies with multiple markers of melanosomes, lysosomes, or endosomes were unable to determine the identity of this punctuate staining (Fig. 3D).”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > NCKX5 Protein Is Located in an Intracellular
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“The expression of early melanosome markers pmel17 (85-kDa form) and MART1 and late melanosomal markers TYR and TYRP1 was substantially reduced after SLC245A5 knockdown.”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > SLC24A5 Knockdown Reduces Melanin Production in NHM-
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In the paper
“Multiple sequence alignments predict that the protein encoded by SLC24A5 is a member of the NCKX protein family (ϳ42% similarity across the whole protein and 70% similarity in the conserved ␣1 and ␣2 regions).”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > SLC24A5 Plays a Key Role in Melanogenesis-In vivo epidermal melanocytes synthesize melanin within specialized
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“We have found no evidence to suggest that NCKX5 is located at the plasma membrane of cultured melanocytes, consistent with previous findings (7), which reported an intracellular localization for tagged recombinant zebrafish NCKX5.”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > SLC24A5 Plays a Key Role in Melanogenesis-In vivo epidermal melanocytes synthesize melanin within specialized
What the sources say
- Not checked yetcites [7] Lamason, 2005, Science source
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In the paper
“However, three other substitutions at residues that differ between NCKX1-4 and NCKX5 in regions of high sequence conservation (A150S, L193F, and I554L) had little impact on NCKX2 activity.”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > SLC24A5 Knockdown Reduces Melanin Production in NHM-
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“However, the level of activity conferred by SLC24A5 was much lower than that generated by SLC24A2 in the same system, possibly reflecting differences in subcellular distribution or the considerably lower expression level observed for NCKX5 compared with NCKX2.”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > SLC24A5 Plays a Key Role in Melanogenesis-In vivo epidermal melanocytes synthesize melanin within specialized
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“In a proteomic analysis of fractionated melanocytes, NCKX5 was detected in melanosomeenriched fractions (18), although we have not detected any colocalization between NCKX5 and melanosomal markers by immunofluorescence microscopy with our antisera (Fig. 3D).”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > SLC24A5 Plays a Key Role in Melanogenesis-In vivo epidermal melanocytes synthesize melanin within specialized
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“Furthermore, the cation dependences did not vary significantly between the two allelic variants of NCKX2 when expressed in HEK293 cells assayed with fluorescent Ca 2ϩ -indicating dyes.”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > SLC24A5 Knockdown Reduces Melanin Production in NHM-
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“The cell surface-localized recombinant NCKX5 generated by heterologous expression of SLC24A5 cDNA in insect High Five cells enabled us to demonstrate for the first time that NCKX5 possesses authentic NCKX activity (Fig. 8C).”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > SLC24A5 Plays a Key Role in Melanogenesis-In vivo epidermal melanocytes synthesize melanin within specialized
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- Rests on an assumption: Currently available methodologies are not suitable for measuring intracellular sodium-calcium exchange activity.
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In the paper
“In addition, the same SLC24A5 siRNA duplexes block de novo pigment production in partially de-differentiated melanocytes grown in melanoblast media and returned to full melanocyte growth media, suggesting that SLC24A5 may operate at an early stage of melanosome biogenesis (Fig. 6B).”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > DISCUSSION
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“In NMH low levels of SLC24A1 and very low levels of SLC24A3 and SLC24A4 were detected, and in the mouse melanocytes, low levels of SLC24A4 and very low levels of SLC24A1 and SLC24A3 were found.”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > SLC24A5 mRNA Is the Predominant Sodium-Calcium Exchanger Transcript in Human and Mouse Melanocytes-In mammalian cells sodium-calcium exchange is mediated both
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In the paper
“In both cultures the predominant isoform was SLC24A5, which was Ͼ100fold more highly expressed than any of the other SLC24A transcripts, and transcripts of the SLC8 family were not detected in either cell line.”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > SLC24A5 mRNA Is the Predominant Sodium-Calcium Exchanger Transcript in Human and Mouse Melanocytes-In mammalian cells sodium-calcium exchange is mediated both
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In the paper
“In both proteins, switching alanine to threonine at the critical residue (NCKX5 residue 111 and NCKX2 residue 177) caused a substantial reduction in exchanger activity.”
- Also stated in: § SLC24A5 Plays a Key Role in Melanogenesis-In vivo epidermal melanocytes synthesize melanin within specialized · plain
“Furthermore, the nsSNP in SLC24A5 associated with natural human skin color variation encodes an amino acid change that alters both NCKX2 and NCKX5 activity.”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > SLC24A5 Plays a Key Role in Melanogenesis-In vivo epidermal melanocytes synthesize melanin within specialized
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- Also stated in: § SLC24A5 Plays a Key Role in Melanogenesis-In vivo epidermal melanocytes synthesize melanin within specialized · 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
“We found no evidence of plasma membrane staining with these antisera using confocal microscopy.”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > NCKX5 Protein Is Located in an Intracellular
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In the paper
“Cultured dark NHM probed by immunofluorescence with either of our anti-NCKX5 antisera, raised against different pep- tides and regions of NCKX5, showed the same strong perinuclear staining and also punctuate staining distributed throughout the cytoplasm (Fig. 2C).”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > NCKX5 Protein Is Located in an Intracellular
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In the paper
“Fractionation of our NHM extracts using a sucrose density gradient similar to that used in the proteomic study (18) revealed that NCKX5, dark pigment, and TGN46 were all enriched in the fractions enriched for melanosomal marker TYRP1.”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > SLC24A5 Plays a Key Role in Melanogenesis-In vivo epidermal melanocytes synthesize melanin within specialized
What the sources say
- Not checked yetcites [18] Chi, 2006, J. Proteome Res. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Data generated using our affinity-purified polyclonal antisera suggest that, unlike other previously characterized members of the sodiumcalcium exchanger and NCKX families, native NCKX5 is located in a subcellular compartment that partially overlaps with a region of the TGN (Figs. 2 and 3).”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > SLC24A5 Plays a Key Role in Melanogenesis-In vivo epidermal melanocytes synthesize melanin within specialized
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In the paper
“Our alternative model takes into account the dramatic effect of SLC24A5 knockdown on pigmentation in re-differentiating melanocytes, and the effect that this has on the expression of pmel17 and Lamp1.”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > SLC24A5 Plays a Key Role in Melanogenesis-In vivo epidermal melanocytes synthesize melanin within specialized
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In the paper
“Our alternative model takes into account the dramatic effect of SLC24A5 knockdown on pigmentation in re-differentiating melanocytes, and the effect that this has on the expression of pmel17 and Lamp1.”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > SLC24A5 Plays a Key Role in Melanogenesis-In vivo epidermal melanocytes synthesize melanin within specialized
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Using high density whole genome array technology, we have defined the key genetic variants associated with natural skin color variation in a population of South Asian ancestry (6).”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > Abstract
What the sources say
- Not checked yetcites [6] Stokowski, 2007, Am. J. Hum. Genet. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Independently, a group of zebrafish researchers discovered that a different mutation in the zebrafish orthologue of this gene was responsible for the hypo-pigmented phenotype of the golden zebrafish (7).”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > Abstract
What the sources say
- Not checked yetcites [7] Lamason, 2005, Science source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“A non-synonymous single nucleotide polymorphism in the human SLC24A5 gene is associated with natural human skin color variation.”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > Abstract
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“We suggest that NCKX5 directly regulates human epidermal melanogenesis and natural skin color through its intracellular potassium-dependent exchanger activity.”
- Also stated in: § Abstract · hedged
“Together, these data support the hypothesis that a nsSNP in the SLC24A5 gene directly alters human skin color through its effect on the sodium-calcium exchanger activity of NCKX5.”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > Abstract
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- Also stated in: § Abstract · hedged
In the paper
“Furthermore, they demonstrated that the allele encoding threonine 111 of the protein encoded by SLC24A5 was associated with lighter skin in an admixed African-American population.”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > Abstract
What the sources say
- Not checked yetcites [7] Lamason, 2005, Science source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Multiple sequence alignments predict that this gene encodes a member of the potassium-dependent sodiumcalcium exchanger family denoted NCKX5.”
- Also stated in: § Abstract · hedged
“Amino acid sequence alignments predict that SLC24A5 encodes a member of the potassium-dependent sodium calcium exchanger protein family, designated NCKX5.”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > Abstract
hedged- Asserted: passes — The authors put it forward as true.
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- Also stated in: § Abstract · hedged
In the paper
“We identified a non-synonymous single nucleotide polymorphism (nsSNP) 2 in the SLC24A5 gene (rs1426654) that was previously unknown to skin pigmentation biologists.”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > Abstract
What the sources say
- Not checked yetcites [6] Stokowski, 2007, Am. J. Hum. Genet. source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“This is consistent with the observation that melanosomal pH is higher in cultured melanocytes derived from Negroid donors compared with those derived from Caucasian donors (29).”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > SLC24A5 Plays a Key Role in Melanogenesis-In vivo epidermal melanocytes synthesize melanin within specialized
What the sources say
- Not checked yetcites [29] Fuller, 2001, Exp. Cell Res. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“The specificity of affinity-purified antisera for native NCKX5 protein was assessed through siRNA-mediated knockdown in NHM.”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > NCKX5 Protein Is Located in an Intracellular
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Treatment with siRNA 762 elicited a marked and reproducible reduction in melanin production 72 h postknockdown (87.7% reduction p Ͻ 0.0001) compared with the control siRNA (Fig. 5, A and B) without any detectable toxicity.”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > SLC24A5 Knockdown Reduces Melanin Production in Mouse B16
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“This region contains a number of residues that are critical for exchange function (14 -16), and the experimentally determined topology for NCKX2 suggests that the polymorphic residue of NCKX5 sits in a transmembrane domain (17).”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > Abstract
What the sources say
- Not checked yetcites [17] Kinjo, 2003, Biochemistry source
hedged- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“This region contains a number of residues that are critical for exchange function (14 -16), and the experimentally determined topology for NCKX2 suggests that the polymorphic residue of NCKX5 sits in a transmembrane domain (17).”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > Abstract
What the sources say
plain- Asserted: passes — The authors put it forward as true.
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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 demonstrates that this gene and its products play a controlling role in melanogenesis in this system.”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > SLC24A5 Knockdown Reduces Melanin Production in Mouse B16
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“A role for NCKX5 in early melanosome biogenesis is also supported by the reduction in partially processed 85-kDa pmel17 protein observed after SLC24A5 knockdown (Fig. 7), as this is a marker of early melanosomes (25).”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > DISCUSSION
What the sources say
- Not checked yetcites [25] Valencia, 2007, J. Biol. Chem. source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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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 suggests that this residue is important for the exchanger activity of both NCKX2 and NCKX5, and a high level of cross-species and cross-family sequence conservation around this residue implies is likely to be important for all NCKX proteins.”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > SLC24A5 Plays a Key Role in Melanogenesis-In vivo epidermal melanocytes synthesize melanin within specialized
hedgeddirect- Asserted: passes — The authors put it forward as true.
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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 suggests that this residue is important for the exchanger activity of both NCKX2 and NCKX5, and a high level of cross-species and cross-family sequence conservation around this residue implies is likely to be important for all NCKX proteins.”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > SLC24A5 Plays a Key Role in Melanogenesis-In vivo epidermal melanocytes synthesize melanin within specialized
hedgedconditional- Asserted: passes — The authors put it forward as true.
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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
“Our knockdown data support a central function for SLC24A5 in mammalian pigmentation, conserved from fish to man.”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > DISCUSSION
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In addition, the same SLC24A5 siRNA duplexes block de novo pigment production in partially de-differentiated melanocytes grown in melanoblast media and returned to full melanocyte growth media, suggesting that SLC24A5 may operate at an early stage of melanosome biogenesis (Fig. 6B).”
- Also stated in: § DISCUSSION · hedged
“that SLC24A5 may operate at an early stage of melanosome biogenesis (Fig. 6B).”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > DISCUSSION
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Also stated in: § DISCUSSION · hedged
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Transfection with two different siRNA duplexes (siRNA 185 and siRNA 492) resulted in Ͼ90% knockdown of SLC24A5 transcript levels compared with control cultures after 48 h.”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > NCKX5 Protein Is Located in an Intracellular
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In a proteomic analysis of fractionated melanocytes, NCKX5 was detected in melanosomeenriched fractions (18), although we have not detected any colocalization between NCKX5 and melanosomal markers by immunofluorescence microscopy with our antisera (Fig. 3D).”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > SLC24A5 Plays a Key Role in Melanogenesis-In vivo epidermal melanocytes synthesize melanin within specialized
What the sources say
- Not checked yetcites [18] Chi, 2006, J. Proteome Res. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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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
“NHM transfected with either of the SLC24A5 knockdown siRNAs (Fig. 6A) resulted in significant percentage reductions of 22 and 30.5% (siRNA 185 and 492, respectively; p Ͻ 0.0001) of total cellular melanin compared with the control cells, demonstrating that SLC24A5 expression plays an important role in melanin synthesis in these cells.”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > SLC24A5 Knockdown Reduces Melanin Production in NHM-
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Treatment of light or dark melanocytes with either of the human siRNA duplexes for 5 days resulted in complete loss of perinuclear NCKX5 in Ͼ90% of cells.”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > NCKX5 Protein Is Located in an Intracellular
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“This is the first demonstration that SLC24A5 is directly involved in human melanogenesis.”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > DISCUSSION
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“These results demonstrate for the first time that SLC24A5 expression is necessary for melanin production in human epidermal melanoblasts stimulated to differentiate.”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > SLC24A5 Knockdown Reduces Melanin Production in NHM-
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“We propose that NCKX5 could play a role in maintaining local calcium concentrations in or near to the coated endosomes, which are closely associated with the TGN (47), to facilitate appropriate membrane fusion”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > SLC24A5 Plays a Key Role in Melanogenesis-In vivo epidermal melanocytes synthesize melanin within specialized
What the sources say
- Not checked yetcites [47] Raposo, 2001, J. Cell Biol. source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“The 85-kDa form of pmel17 that is down-regulated by SLC24A5 knockdown is a marker of early melanosomes (25), whereas Lamp1 is enriched in lysosomes (47).”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > SLC24A5 Plays a Key Role in Melanogenesis-In vivo epidermal melanocytes synthesize melanin within specialized
What the sources say
- Not checked yetcites [25] Valencia, 2007, J. Biol. Chem. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“We have shown that NCKX5 is localized to the TGN of epidermal melanocytes and plays a direct and important role in human melanogenesis.”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > SLC24A5 Plays a Key Role in Melanogenesis-In vivo epidermal melanocytes synthesize melanin within specialized
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Consequently, protein and membrane resources from within the coated endosome are diverted into the endosome-lysosome pathway, leading to an up-regulation of Lamp1.”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > SLC24A5 Plays a Key Role in Melanogenesis-In vivo epidermal melanocytes synthesize melanin within specialized
plaindirect- Asserted: passes — The authors put it forward as true.
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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 strongly suggests that NCKX5 exchange function modulates melanogenesis in epidermal melanocytes and thereby in human skin.”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > SLC24A5 Plays a Key Role in Melanogenesis-In vivo epidermal melanocytes synthesize melanin within specialized
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Probably not a substantial claim. 12
- It may state two separate claims as one. 12
Every source the paper cites for this claim was checked and supports it.
In the paper
“The Golgi apparatus is an established calcium store (31), and its role in sorting and processing secretory and membrane proteins is highly sensitive to changes in calcium concentration within the lumen.”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > SLC24A5 Plays a Key Role in Melanogenesis-In vivo epidermal melanocytes synthesize melanin within specialized
What the sources say
- Supportedcites [31] Pinton, 1998, EMBO J. source
The Discussion describes the Golgi as “a bona fide store of rapidly mobilizable Ca²⁺” and reports agonist-dependent calcium discharge from it. This supports the cited clause that the Golgi apparatus is a calcium store. (LLM, conf=0.93)
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Probably not a substantial claim.
- 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
“In NMH low levels of SLC24A1 and very low levels of SLC24A3 and SLC24A4 were detected, and in the mouse melanocytes, low levels of SLC24A4 and very low levels of SLC24A1 and SLC24A3 were found.”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > SLC24A5 mRNA Is the Predominant Sodium-Calcium Exchanger Transcript in Human and Mouse Melanocytes-In mammalian cells sodium-calcium exchange is mediated both
plain- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
It 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
“Constructs carrying the threonine variant had a greatly reduced exchange activity compared with those carrying the alanine variant (Fig. 8C).”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > SLC24A5 Knockdown Reduces Melanin Production in NHM-
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
“A similar pattern of staining was observed in both light and dark NHM, although the perinuclear staining was less intense in lighter melanocytes.”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > NCKX5 Protein Is Located in an Intracellular
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
“The apparent size of these bands is surprisingly low compared with the predicted molecular mass in the absence of glycosylation of 54.9 kDa.”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > NCKX5 Protein Is Located in an Intracellular
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
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
“Reverse exchange of NCKX5 was only observed when extracellular K ϩ was present and no reverse exchange was observed in the presence of either extracellular Na ϩ or Li ϩ , confirming K ϩ -dependent Na ϩ /Ca 2ϩ exchange function.”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > SLC24A5 Knockdown Reduces Melanin Production in NHM-
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The 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
“Thus, when SLC24A5 is disrupted through siRNA knockdown, melanosomal maturation is blocked, leading to a down-regulation of pmel17 and late melanosomal markers TYR and TYRP1.”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > SLC24A5 Plays a Key Role in Melanogenesis-In vivo epidermal melanocytes synthesize melanin within specialized
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Subsequent analyses have pinpointed this SNP and another in the SLC45A2 gene as participants in the evolution of light skin in Europeans but not East Asians (9 -11).”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > Abstract
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
“De-glycosylation of the recombinant protein (Fig. 2B) removes the upper band, suggesting that the lower bands reflect signal peptide cleavage of unglycosylated protein.”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > NCKX5 Protein Is Located in an Intracellular
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
“Conversely, expression of the lysosomal marker LAMP-1 was up-regulated after SLC24A5 knockdown, suggesting that SLC24A5 plays a role very early in melanosome biogenesis and that this process is intimately linked with lysosome biogenesis.”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > SLC24A5 Knockdown Reduces Melanin Production in NHM-
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“This might account for the reduced tyrosinase activity measured in Caucasian compared with Negroid-derived melanocytes (30).”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > SLC24A5 Plays a Key Role in Melanogenesis-In vivo epidermal melanocytes synthesize melanin within specialized
What the sources say
- Not checked yetcites [30] Iozumi, 1993, J. Investig. Dermatol. source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
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 data also support the hypothesis that the nsSNP associated with skin color variation is causative, directly mediating phenotypic variation in skin color by altering NCKX5 exchanger activity.”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > SLC24A5 Plays a Key Role in Melanogenesis-In vivo epidermal melanocytes synthesize melanin within specialized
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“These data, supporting an intracellular, partial TGN localization, are surprising since all other NCKX proteins have been shown to traffic to the plasma membrane where they operate to remove Ca 2ϩ from the cytoplasm to the extracellular space (26 -28).”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > SLC24A5 Plays a Key Role in Melanogenesis-In vivo epidermal melanocytes synthesize melanin within specialized
What the sources say
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“The NCKX family currently consists of five members (NCKX 1-5) that are thought to use both the inward sodium gradient and the outward potassium gradient to extrude calcium across the plasma membrane.”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > Abstract
What the sources say
- Not checked yetcites [12] Altimimi, 2007, Channels source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“The 85-kDa form of pmel17 that is down-regulated by SLC24A5 knockdown is a marker of early melanosomes (25), whereas Lamp1 is enriched in lysosomes (47).”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > SLC24A5 Plays a Key Role in Melanogenesis-In vivo epidermal melanocytes synthesize melanin within specialized
What the sources say
- Not checked yetcites [47] Raposo, 2001, J. Cell Biol. source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“In addition, the Na ϩ /H ϩ exchanger NHE7 is located in the TGN and post-Golgi vesicles (35,36) and is differentially expressed in light and dark NHM (37) melanosomal pH could also be applied to the TGN.”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > SLC24A5 Plays a Key Role in Melanogenesis-In vivo epidermal melanocytes synthesize melanin within specialized
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
In the paper
“Ca 2ϩ is also a co-factor for phenylalanine hydroxylase (45); the latter has been suggested to protect the redox balance and prevent DNA damage (46).”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > SLC24A5 Plays a Key Role in Melanogenesis-In vivo epidermal melanocytes synthesize melanin within specialized
What the sources say
- Not checked yetcites [45] Schallreuter, 1999, Biochem. Biophys. Res. Commun. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Endosomal membrane fusion events, which are essential processes in melanosome and lysosome-related organelle biogenesis, are Ca 2ϩ -mediated (49, 50) and are likely modulated by changing local Ca 2ϩ gradients.”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > SLC24A5 Plays a Key Role in Melanogenesis-In vivo epidermal melanocytes synthesize melanin within specialized
What the sources say
- Not checked yetcites [49] Mayorga, 1994, J. Cell Biol.
- Not checked yetcites [50] Pryor, 2000, J. Cell Biol. source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“In the model proposed by Raposo et al. (47,48), the coated endosome (also referred to as a stage 1 melanosome) serves as a critical sorting point between endocytic and pre-melanosomal pathways, from which macromolecules are specifically directed into melanosomal or lysosomal pathways.”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > SLC24A5 Plays a Key Role in Melanogenesis-In vivo epidermal melanocytes synthesize melanin within specialized
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably 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
“In this model NCKX5 is required for the correct delivery of melanosomal components such as pmel17 into the melanosomal pathway.”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > SLC24A5 Plays a Key Role in Melanogenesis-In vivo epidermal melanocytes synthesize melanin within specialized
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
In the paper
“The importance of correctly regulating such intracellular trafficking mechanisms to melanogenesis is highlighted by the de-pigmenting effects of certain tricyclic compounds that elicit the mis-trafficking of tyrosinase leading to its co-localization with Lamp1 (51).”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > SLC24A5 Plays a Key Role in Melanogenesis-In vivo epidermal melanocytes synthesize melanin within specialized
What the sources say
- Not checked yetcites [51] Ni-Komatsu, 2007, J. Investig. Dermatol.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Recent work has shown that the calcium concentration of the Golgi compartment is highly regulated in keratinocytes (32,33), and the calcium gradients across the Golgi play a fundamental part in intracellular calcium signaling and homeostasis (for review, see Ref. 34).”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > SLC24A5 Plays a Key Role in Melanogenesis-In vivo epidermal melanocytes synthesize melanin within specialized
What the sources say
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
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
“We, therefore, propose a second model in which NCKX5 modulates melanogenesis through a role in the trafficking/sorting decisions, which occur within the coated endosome.”
§ SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis * > SLC24A5 Plays a Key Role in Melanogenesis-In vivo epidermal melanocytes synthesize melanin within specialized
hedgeddirect- Asserted: fails — The authors may not put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The authors may not put it forward as true.
The paper relies on this without support.
The exchanger activity of NCKX5 has not yet been experimentally demonstrated.
“Although SLC24A5 is predicted to encode an NCKX protein, the exchanger activity of NCKX5 has yet to be experimentally demonstrated.”
The paper relies on this without support.
NCKX5's credentials as a sodium-calcium-potassium exchanger had not previously been established experimentally.
“However, despite a high degree of similarity at the amino acid level (Fig. 8B), the credentials of NCKX5 as a sodium-calcium-potassium exchanger have not previously been established experimentally.”
The paper relies on this without support.
Currently available methodologies are not suitable for measuring intracellular sodium-calcium exchange activity.
“The unique intracellular localization of NCKX5 necessitates the development of new assays as the currently available methodologies are not suitable for measuring intracellular sodium-calcium exchange activity.”
The paper relies on this without support.
The more alkaline environment of Negroid melanosomes favors the activity of tyrosinase.
“The more alkaline environment of Negroid melanosomes is believed to favor the activity of tyrosinase, a rate-limiting catalyst of melanin synthesis that operates optimally at neutral pH.”
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?
In the citing paper
“The involvement of NCKX5 in this process is highly likely given the role of this family of proteins in transmembrane Ca 2 þ transport (Schnetkamp, 2004), and the higher ion exchange activity of NCKX5-111A compared to NCKX5-111T (Ginger et al., 2008).”
From Analysis of Cultured Human Melanocytes Based on Polymorphisms within the SLC45A2/MATP, SLC24A5/NCKX5, and OCA2/P Loci (2009) · cites this paper as Ginger et al., 2008
Citations
Cites
A haplotype map of the human genome
The International HapMap Consortium (2005) · Nature · doi:10.1038/nature04226 · Cited by 5,858
The Jalview Java alignment editor
Clamp, M. E., Cuff, J. A., Searle, S. M. J., & Barton, G. J. (2004) · Bioinformatics · doi:10.1093/bioinformatics/btg430 · Cited by 1,578
SLC24A5, a putative cation exchanger, affects pigmentation in zebrafish and humans
Lamason, R. L., Mohideen, M.-A. P. K., Mest, J. R., Wong, A. C., Norton, H. L., Aros, M. C., Jurynec, M. J., Mao, X., Humphreville, V. R., Humbert, J. E., et al. (2005) · Science · doi:10.1126/science.1116238 · Cited by 1,043
Mutations in ATP2C1, encoding a calcium pump, cause Hailey-Hailey disease
Hu, Z., Bonifas, J. M., Beech, J., Bench, G., Shigihara, T., Ogawa, H., Ikeda, S., Mauro, T., & Epstein, E. H. (2000) · Nature Genetics · doi:10.1038/71701 · Cited by 567
Skin pigmentation, biogeographical ancestry and admixture mapping
Shriver, M. D., Parra, E. J., Dios, S., Bonilla, C., Norton, H., Jovel, C., Pfaff, C., Jones, C., Massac, A., Cameron, N., et al. (2003) · Human Genetics · doi:10.1007/s00439-002-0896-y · Cited by 549
Raposo, G., Tenza, D., Murphy, D. M., Berson, J. F., & Marks, M. S. (2001) · The Journal of Cell Biology · doi:10.1083/jcb.152.4.809 · Cited by 451
Pinton, P., Pozzan, T., & Rizzuto, R. (1998) · The EMBO Journal · doi:10.1093/emboj/17.18.5298 · Cited by 435
Genetic evidence for the convergent evolution of light skin in Europeans and East Asians
Norton, H. L., Kittles, R. A., Parra, E., McKeigue, P., Mao, X., Cheng, K., Canfield, V. A., Bradley, D. G., McEvoy, B., & Shriver, M. D. (2006) · Molecular Biology and Evolution · doi:10.1093/molbev/msl203 · Cited by 410
Human pigmentation genes: identification, structure and consequences of polymorphic variation
Sturm, R. A., Teasdale, R. D., & Box, N. F. (2001) · Gene · doi:10.1016/s0378-1119(01)00694-1 · Cited by 398
Nakamura, N., Tanaka, S., Teko, Y., Mitsui, K., & Kanazawa, H. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m410041200 · Cited by 353
Research works printed but not linked: 4
- Soejima, 2007, Int. J. Med., 121, 36
- Kang, 1998, Pfluegers Arch. Eur. J. Physiol., 435, 350
- Mayorga, 1994, J. Cell Biol., 269, 30927
- Ni-Komatsu, 2007, J. Investig. Dermatol.
Cited by
Sorted by citations
NCLX is an essential component of mitochondrial Na + /Ca 2+ exchange
Palty, R., Silverman, W. F., Hershfinkel, M., Caporale, T., Sensi, S. L., Parnis, J., Nolte, C., Fishman, D., Shoshan‐Barmatz, V., Herrmann, S., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0908099107 · Cited by 789
Molecular genetics of human pigmentation diversity
Sturm, R. A. (2009) · Human Molecular Genetics · doi:10.1093/hmg/ddp003 · Cited by 379
Anatomy and Organization of Human Skin
McGrath, J. A., Eady, R. A. J., & Pope, F. M. (2004) · Wiley eBooks · doi:10.1002/9780470750520.ch3 · Cited by 327
Acidic calcium stores open for business: expanding the potential for intracellular Ca2+ signaling
Patel, S., & Docampo, R. (2010) · Trends in Cell Biology · doi:10.1016/j.tcb.2010.02.003 · Cited by 237
Update on the regulation of mammalian melanocyte function and skin pigmentation
Kondo, T., & Hearing, V. J. (2011) · Expert Review of Dermatology · doi:10.1586/edm.10.70 · Cited by 207
Metadata
- Authors
- Ginger, R. S., Askew, S. E., Ogborne, R. M., Wilson, S., Ferdinando, D., Dadd, T., Smith, A. M., Kazi, S., Szerencsei, R. T., Winkfein, R. J., Schnetkamp, P. P. M., & Green, M. R.
- Affiliations
- Unilever (United Kingdom) (GB)
- University of Calgary (CA)
- Corresponding author
- Ginger, Rebecca S.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2008-02
- Volume
- 283
- Issue
- 9
- Pages
- 5486-5495
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2109627824
- Cited by
- 158
- References
- 49
- Citations by year
- 2026: 3 · 2025: 10 · 2024: 4 · 2023: 3 · 2022: 9 · 2021: 8 · 2020: 14 · 2019: 7 · 2018: 10 · 2017: 8 · 2016: 8 · 2015: 7 · 2014: 10 · 2013: 11 · 2012: 9
- FWCI
- 3.58
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › melanin and skin pigmentation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
- Keywords
- SLC24A5, NCKX2, Na+/Ca2+ exchanger, melanogenesis, melanocytes, trans-Golgi network, skin color variation, single nucleotide polymorphisms
- MeSH terms
- Animals, Calcium, Golgi Apparatus, Humans, Male, Melanins, Melanocytes, Pigmentation, Potassium, Sodium, Ion Transport, Antiporters, Sodium-Calcium Exchanger, Polymorphism, Single Nucleotide, Cell Line, Tumor, Mice
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 2026-10-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-10 (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.
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