SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis

Ginger, Rebecca S.; Askew, Sarah E.; Ogborne, Richard M.; Wilson, Stephen W.; Ferdinando, Dudley; Dadd, Tony; Smith, Adrian; Kazi, Shubana; Szerencsei, Robert T.; Winkfein, Robert J.; Schnetkamp, Paul P. M.; Green, Martin R.

doi:10.1074/jbc.m707521200

Cited by 144 publications

(132 citation statements)

References 48 publications

(60 reference statements)

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“…Tyrosinase contains 15 lumenal Cys residues and many intramolecular disulfide bonds (Wang and Hebert, 2006), so changes in the disulfide bonding capacity of the ER could have a significant effect on tyrosinase maturation. A similar indirect effect on cellular ion levels and consequent tyrosinase missorting has been hypothesized to underlie the pigmentation defects in cells bearing a mutated form of SLC24A5, a pigment cell-specific potassium-dependent sodium-calcium exchanger that was suggested to localize to the trans-Golgi network (Ginger et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Localization to Mature Melanosomes by Virtue of Cytoplasmic Dileucine Motifs Is Required for Human OCA2 Function

Sitaram

Piccirillo

Palmisano

et al. 2009

MBoC

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Oculocutaneous albinism type 2 is caused by defects in the gene OCA2, encoding a pigment cell-specific, 12-transmembrane domain protein with homology to ion permeases. The function of the OCA2 protein remains unknown, and its subcellular localization is under debate. Here, we show that endogenous OCA2 in melanocytic cells rapidly exits the endoplasmic reticulum (ER) and thus does not behave as a resident ER protein. Consistently, exogenously expressed OCA2 localizes within melanocytes to melanosomes, and, like other melanosomal proteins, localizes to lysosomes when expressed in nonpigment cells. Mutagenized OCA2 transgenes stimulate melanin synthesis in OCA2-deficient cells when localized to melanosomes but not when specifically retained in the ER, contradicting a proposed primary function for OCA2 in the ER. Steady-state melanosomal localization requires a conserved consensus acidic dileucine-based sorting motif within the cytoplasmic N-terminal region of OCA2. A second dileucine signal within this region confers steadystate lysosomal localization in melanocytes, suggesting that OCA2 might traverse multiple sequential or parallel trafficking routes. The two dileucine signals physically interact in a differential manner with cytoplasmic adaptors known to function in trafficking other proteins to melanosomes. We conclude that OCA2 is targeted to and functions within melanosomes but that residence within melanosomes may be regulated by secondary or alternative targeting to lysosomes. INTRODUCTIONMelanin pigments are synthesized by specialized cell types, including dermal and epidermal melanocytes and retinal pigment epithelial cells, within unique organelles known as melanosomes . Melanosomes are members of a class of tissue-specific "lysosome-related organelles" characterized by an acidic lumenal pH and the presence of some lysosomal proteins (Dell'Angelica et al., 2000;Griffiths, 2002). Among lysosome-related organelles, melanosomes represent a subclass that coexists with bona fide lysosomes in their host cells . Melanosomes are distinguished from lysosomes by the presence of cell-type-specific cargo proteins that confer unique functional and morphological properties. How these cargo proteins are diverted from traditional lysosomes and delivered to and maintained within melanosomes is incompletely understood, and the degree of cargo cross-talk between melanosomes and lysosomes is not known.Melanosomes undergo a program of maturation within melanocytes by the ordered delivery of cargoes to nascent melanosomes via specialized trafficking pathways . Some components of the melanosomal trafficking machinery are known, largely from analyses of the sorting of well-characterized cargo proteins, such as the melanogenic enzyme tyrosinase (Tyr) and tyrosinase-related protein 1 (Tyrp1), in both wild-type melanocytes and melanocytes derived from patients or mouse models of genetic hypopigmentary diseases such as Hermansky-Pudlak Syndrome (HPS) (Di Pietro and Dell'Angelica, 2005;Wei, 2006). Tyr and Tyrp1 contain cytoplasmic a...

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Section: Discussionmentioning

confidence: 99%

Localization to Mature Melanosomes by Virtue of Cytoplasmic Dileucine Motifs Is Required for Human OCA2 Function

Sitaram

Piccirillo

Palmisano

et al. 2009

MBoC

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“…Newton et al reported the up-regulation of MATP by NDP-MSH, which is abolished in melanocytes expressing RHC variants for MC1R (45). Slc24a5, also regulates melanogenesis (42,46) and is downregulated in yellow quails overexpressing agouti (47). In addition to the inhibitory effects of ASP on proteins related to melanosome maturation and function, ASP also modulated genes encoding proteins involved in melanosome transport, such as Rab27a, Rab38, and Hps3.…”

Section: Figmentioning

confidence: 99%

Microarray analysis sheds light on the dedifferentiating role of agouti signal protein in murine melanocytes via the Mc1r

Pape

Passeron

Giubellino

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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The melanocortin-1 receptor (MC1R) is a key regulator of pigmentation in mammals and is tightly linked to an increased risk of skin cancers, including melanoma, in humans. Physiologically activated by ␣-melanocyte stimulating hormone (␣MSH), MC1R function can be antagonized by a secreted factor, agouti signal protein (ASP), which is responsible for the lighter phenotypes in mammals (including humans), and is also associated with increased risk of skin cancer. It is therefore of great interest to characterize the molecular effects elicited by those MC1R ligands. In this study, we determined the gene expression profiles of murine melan-a melanocytes treated with ASP or ␣MSH over a 4-day time course using genome-wide oligonucleotide microarrays. As expected, there were significant reductions in expression of numerous melanogenic proteins elicited by ASP, which correlates with its inhibition of pigmentation. ASP also unexpectedly modulated the expression of genes involved in various other cellular pathways, including glutathione synthesis and redox metabolism. Many genes up-regulated by ASP are involved in morphogenesis (especially in nervous system development), cell adhesion, and extracellular matrix-receptor interactions. Concomitantly, ASP enhanced the migratory potential and the invasiveness of melanocytic cells in vitro. These results demonstrate the role of ASP in the dedifferentiation of melanocytes, identify pigment-related genes targeted by ASP and by ␣MSH, and provide insights into the pleiotropic molecular effects of MC1R signaling that may function during development and may affect skin cancer risk.pigmentation ͉ skin cancer A major determinant of the pigment phenotype of the skin is the melanocortin-1 receptor (MC1R), a G protein coupled receptor (GPCR) that regulates many functional aspects of melanocytes, including their dendricity, melanogenesis, and proliferation (1, 2). MC1R function can be activated by ␣-melanocyte-stimulating hormone (␣MSH), a POMC-derived peptide whose production in the skin (3) is increased by exposure to UV radiation (UV) via a p53-dependent mechanism (4). This interaction triggers increased melanin production (5, 6) and stimulates the repair of DNA photoproducts caused by UV (7-9), a phenomenon also induced by forskolin (10). It is therefore not surprising that MC1R polymorphisms are associated with a lighter pigment phenotype, including red hair/fair skin (11), with poor tanning responses (12) and an increased risk for melanoma and other skin cancers (13,14).MC1R signaling can be inhibited by the product of the agouti locus, agouti signal protein (ASP in mice, ASIP in humans), which acts as an inverse agonist of the murine Mc1r (15,16). In mice, ASP is expressed in skin and testis and during embryogenesis. The spatiotemporal expression of ASP in skin is responsible for the agouti hair phenotype (a pheomelanic band against a dark eumelanic background) and for the pale coloration on the neck, breast, and ventral surface (17). A high degree of polymorphism in the promoter of t...

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“…In mammalian cells, Ca 2ϩ uptake is mediated by either sarco/ endoplasmic reticulum Ca 2ϩ -ATPases (SERCAs) or secretory pathway Ca 2ϩ -ATPases, located in the Golgi complex and secretory granules (17,18). In addition, acidic organelles have a large concentration gradient of protons that has been reported to be necessary to maintain Ca 2ϩ accumulated (19,20), probably by supporting a Ca 2ϩ /H ϩ exchange mechanism mediated by the cooperative activity of Na ϩ /H ϩ and Na ϩ /Ca 2ϩ exchangers (21)(22). The proton gradient in acidic organelles is maintained by a vacuolar proton-ATPase (V-ATPase) that drives acidification (23)(24).…”

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confidence: 99%

STIM1 and STIM2 Are Located in the Acidic Ca2+ Stores and Associates with Orai1 upon Depletion of the Acidic Stores in Human Platelets

Zbidi

Jardín

Woodard

et al. 2011

Journal of Biological Chemistry

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Mammalian cells accumulate Ca2؉ into agonist-sensitive acidic organelles, vesicles that possess a vacuolar protonATPase. Acidic Ca 2؉ stores include secretory granules and lysosome-related organelles. Current evidence clearly indicates that acidic Ca 2؉ stores participate in cell signaling and function, including the activation of store-operated Ca 2؉ entry in human platelets upon depletion of the acidic stores, although the mechanism underlying the activation of store-operated Ca 2؉ entry controlled by the acidic stores remains unclear. STIM1 has been presented as the endoplasmic reticulum Ca 2؉ sensor, but its role sensing intraluminal Ca 2؉ concentration in the acidic stores has not been investigated. Here we report that STIM1 and STIM2 are expressed in the lysosome-related organelles and dense granules in human platelets isolated by immunomagnetic sorting. Depletion of the acidic Ca 2؉ stores using the specific vacuolar proton-ATPase inhibitor, bafilomycin A1, enhanced the association between STIM1 and STIM2 as well as between these proteins and the plasma membrane channel Orai1. Depletion of the acidic Ca 2؉ stores also induces time-dependent co-immunoprecipitation of STIM1 with the TRPC proteins hTRPC1 and hTRPC6, as well as between Orai1 and both TRPC proteins. In addition, bafilomycin A1 enhanced the association between STIM2 and SERCA3. These findings demonstrate the location of STIM1 and STIM2 in the acidic Ca 2؉ stores and their association with Ca 2؉ channels and ATPases upon acidic stores discharge.Store-operated calcium entry (SOCE), 4 a Ca 2ϩ influx mechanism regulated by the filling state of the intracellular Ca 2ϩ stores, is a major mechanism for Ca 2ϩ influx in non-excitable cells (1). It has long been known that Ca 2ϩ is stored in the endoplasmic reticulum (ER), which is the best-studied agonistreleasable Ca 2ϩ store; however, a number of studies have revealed that Ca 2ϩ is also dynamically accumulated in a number of acidic organelles (2), including secretory granules, lysosomes and lysosome-related organelles, endosomes, and vesicles of the Golgi complex (2-6). ER Ca 2ϩ store depletion has been reported to be sensed by STIM1 (stromal interaction molecule-1) (7-9). Although STIM1 was originally identified as a surface membrane protein in stromal cells (10) 4 The abbreviations used are: SOCE, store-operated calcium entry; ER, endoplasmic reticulum; HBS, HEPES-buffered saline; hTRPC1 and hTRPC6, human canonical TRP1 and TRP6, respectively; IP 3 , inositol 1,4,5-trisphosphate; TBHQ, 2,5-di-(tert-butyl)-1,4-hydroquinone; TG, thapsigargin; SERCA, sarco/endoplasmic reticulum Ca 2ϩ -ATPase; V-ATPase, vacuolar proton-ATPase; NAADP, nicotinic acid adenine dinucleotide phosphate; DTS, dense tubular system; AM, acetoxymethyl ester; BAPTA-AM, 1,2-bis(2-aminophenoxy)ethane-N,N,NЈ,NЈ-tetraacetic acid tetrakis(acetoxymethyl ester); GPN, glycyl-1-phenylalanine 2-naphthylamide; PDI, protein-disulfide isomerase.

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SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis

Cited by 144 publications

References 48 publications

Localization to Mature Melanosomes by Virtue of Cytoplasmic Dileucine Motifs Is Required for Human OCA2 Function

Localization to Mature Melanosomes by Virtue of Cytoplasmic Dileucine Motifs Is Required for Human OCA2 Function

Microarray analysis sheds light on the dedifferentiating role of agouti signal protein in murine melanocytes via the Mc1r

STIM1 and STIM2 Are Located in the Acidic Ca2+ Stores and Associates with Orai1 upon Depletion of the Acidic Stores in Human Platelets

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