Sorting of Pmel17 to melanosomes through the plasma membrane by AP1 and AP2: evidence for the polarized nature of melanocytes

Valencia, Julio C.; Watabe, Hidenori; Chen, An; Rouzaud, François; Chen, Kevin G.; Vieira, Wilfred D.; Takahashi, Kazutaka; Yamaguchi, Yuji; Berens, Werner; Nagashima, Kunio; Shabanowitz, Jeffrey; Hunt, Donald F.; Appella, Ettore; Hearing, Vincent J.

doi:10.1242/jcs.02804

Cited by 54 publications

(69 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Rab34 interacts with Rab7 [28] and Rab20 is associated with the polarized sorting of V-ATPase, a critical component of the pH regulating machinery in melanosomes. This is consistent with the proposed route of some proteins trafficking directly from the Golgi to melanosomes [29] and the polarized sorting of elements to melanosomes [30]. In addition, Rab-27A plays a crucial role in melanosome dispersion in melanocytes [31], and Rab38 has been shown to have a specific function in melanosomes and maps to a coat color locus in mice [32], although they are also found in dense granules of platelets [33] and in ER [34].…”

Section: Proteins Shared Among Lros-amongsupporting

confidence: 82%

Comparative bioinformatics analyses and profiling of lysosome-related organelle proteomes

Valencia

Huang

et al. 2007

International Journal of Mass Spectrometry

Self Cite

View full text Add to dashboard Cite

Complete and accurate profiling of cellular organelle proteomes, while challenging, is important for the understanding of detailed cellular processes at the organelle level. Mass spectrometry technologies coupled with bioinformatics analysis provide an effective approach for protein identification and functional interpretation of organelle proteomes. In this study, we have compiled human organelle reference datasets from large-scale proteomic studies and protein databases for 7 lysosome-related organelles (LROs), as well as the endoplasmic reticulum and mitochondria, for comparative organelle proteome analysis. Heterogeneous sources of human organelle proteins and rodent homologs are mapped to human UniProtKB protein entries based on ID and/or peptide mappings, followed by functional annotation and categorization using the iProXpress proteomic expression analysis system. Cataloging organelle proteomes allows close examination of both shared and unique proteins among various LROs and reveals their functional relevance. The proteomic comparisons show that LROs are a closely related family of organelles. The shared proteins indicate the dynamic and hybrid nature of LROs, while the unique transmembrane proteins may represent additional candidate marker proteins for LROs. This comparative analysis, therefore, provides a basis for hypothesis formulation and experimental validation of organelle proteins and their functional roles.

show abstract

Section: Proteins Shared Among Lros-amongsupporting

confidence: 82%

Comparative bioinformatics analyses and profiling of lysosome-related organelle proteomes

Valencia

Huang

et al. 2007

International Journal of Mass Spectrometry

Self Cite

View full text Add to dashboard Cite

show abstract

“…3). Thus, we conclude that ␣PEP25h specifically recognizes and identifies iPmel17 localized on the internal side of stage I and II melanosomal membranes and in the plasma membrane, which confirms the sorting of this protein through the secretory pathway to melanosomes (14). Reactivity of ␣PEP25h with intramelanosomal fibrils may reflect the loss of the epitope by cleavage (19) or because of melanin deposition, or it may indicate that iPmel17 is not incorporated into those fibrils.…”

Section: Resultssupporting

confidence: 63%

“…Based on data in this study, the divergence into iPmel17 and mPmel17 may occur in the medial-or trans-Golgi compartments because of different sialylation and glycosylation patterns. Those distinct forms of Pmel17 then sort directly or indirectly to melanosomes as proposed previously (14). Once in stage I melanosomes, mPmel17 is immediately cleaved and forms fibrils critical to the maturation of stage II melanosomes.…”

Section: Transfer Of Sialic Acid To Core 1 O-glycans Is Reduced In Mnmentioning

confidence: 70%

“…Reverse transcription was performed using 200 ng of cytoplasmic RNA as reported previously (14). All amplified products were sequence-verified.…”

Section: Methodsmentioning

confidence: 99%

“…In contrast, no information for the O-glycan content of Pmel17 is available. Recently, we reported that a glycoform of Pmel17 (iPmel17) is sorted via the plasma membrane in a manner distinct from mPmel17, which is sorted directly to melanosomes (14). These facts suggest that Pmel17 can be glycosylated differently and that those forms may have distinct functions.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Sialylated Core 1 O-Glycans Influence the Sorting of Pmel17/gp100 and Determine Its Capacity to Form Fibrils

Valencia

Rouzaud

Julien

et al. 2007

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Pmel17 is a melanocyte/melanoma-specific protein that is essential for the maturation of melanosomes to form mature, fibrillar, and pigmented organelles. Recently, we reported that the less glycosylated form of Pmel17 (termed iPmel17) is sorted via the plasma membrane in a manner distinct from mature Pmel17 (termed mPmel17), which is sorted directly to melanosomes. To clarify the mechanism(s) underlying the distinct processing and sorting of Pmel17, we generated a highly specific antibody (termed ␣PEP25h) against an epitope within the repeat domain of Pmel17 that is sensitive to changes in O-glycosylation. ␣PEP25h recognizes only iPmel17 and allows analysis of the processing and sorting of iPmel17 when compared with ␣PEP13h, an antibody that recognizes both iPmel17 and mPmel17. Our novel findings using ␣PEP25h demonstrate that iPmel17 differs from mPmel17 not only in its sensitivity to endoglycosidase H, but also in the content of core 1 O-glycans modified with sialic acid. This evidence reveals that iPmel17 is glycosylated differently in the Golgi and that it is sorted through the secretory pathway. Analysis of Pmel17 processing in glycosylation-deficient mutant cells reveals that Pmel17 lacking the correct addition of sialic acid and galactose loses the ability to form fibrils. Furthermore, we show that addition of sialic acid affects the stability and sorting of Pmel17 and reduces pigmentation. Alterations in sialyltransferase activity and substrates differ between normal and transformed melanocytes and may represent a critical change during malignant transformation.The human PMEL17 gene encodes two type I integral membrane proteins that are translated from alternatively spliced mRNAs. Those two proteins, known as Pmel17 and gp100, differ as to whether they include a 7-amino acid motif in the membrane proximal region of the luminal domain (1-3). Pmel17 is critical to the formation of an internal fibrillar matrix within stage II melanosomes that is essential to the maturation of that organelle and the subsequent synthesis and deposition of melanin within it. Pmel17 is synthesized as a 68.6-kDa protein, as deduced from the cloned cDNA (2). It is rapidly and quantitatively glycosylated to an "immature" ϳ95-kDa form (termed iPmel17), but only a limited amount is further processed to a "mature" ϳ115-kDa form (termed mPmel17), due at least in part to N-glycosylation at five possible sites (4). mPmel17 can then be cleaved by a furin-like proprotein convertase that generates two fragments, one small fragment (cPmel17, ϳ26 kDa) containing the transmembrane (TM) 3 and the C-terminal domains, and the other larger fragment contains the N-terminal region (5). Those fragments can remain bound to each other by S-S bonds (5, 6). However, the iPmel17 formed remains fully endoglycosidase H (EndoH)-sensitive (4) and is significantly more stable over time than either of the other forms of Pmel17 (mPmel17 and cPmel17) (5).N-Linked core glycosylation begins in the ER and is essential for the function, stability, folding, intrace...

show abstract

Physiological factors that regulate skin pigmentation

2009

Self Cite

View full text Add to dashboard Cite

More than 150 genes have been identified that affect skin color either directly or indirectly, and we review current understanding of physiological factors that regulate skin pigmentation. We focus on melanosome biogenesis, transport and transfer, melanogenic regulators in melanocytes and factors derived from keratinocytes, fibroblasts, endothelial cells, hormones, inflammatory cells and nerves. Enzymatic components of melanosomes include tyrosinase, tyrosinase-related protein 1 and dopachrome tautomerase, which depend on the functions of OA1, P, MATP, ATP7A and BLOC-1 to synthesize eumelanins and pheomelanins. The main structural component of melanosomes is Pmel17/gp100/Silv, whose sorting involves adaptor protein 1A (AP1A), AP1B, AP2 and spectrin, as well as a chaperone-like component, MART-1. During their maturation, melanosomes move from the perinuclear area toward the plasma membrane. Microtubules, dynein, kinesin, actin filaments, Rab27a, melanophilin, myosin Va and Slp2-a are involved in melanosome transport. Foxn1 and p53 up-regulate skin pigmentation via bFGF and POMC derivatives including α-MSH and ACTH, respectively. Other critical factors that affect skin pigmentation include MC1R, CREB, ASP, MITF, PAX3, SOX9/10, LEF-1/TCF, PAR-2, DKK1, SCF, HGF, GM-CSF, endothelin-1, prostaglandins, leukotrienes, thromboxanes, neurotrophins and neuropeptides. UV radiation up-regulates most factors that increase melanogenesis. Further studies will elucidate the currently unknown functions of many other pigment genes/proteins.

show abstract

Sorting of Pmel17 to melanosomes through the plasma membrane by AP1 and AP2: evidence for the polarized nature of melanocytes

Cited by 54 publications

References 43 publications

Comparative bioinformatics analyses and profiling of lysosome-related organelle proteomes

Comparative bioinformatics analyses and profiling of lysosome-related organelle proteomes

Sialylated Core 1 O-Glycans Influence the Sorting of Pmel17/gp100 and Determine Its Capacity to Form Fibrils

Physiological factors that regulate skin pigmentation

Contact Info

Product

Resources

About