title: Glycoprotein nonmetastatic melanoma protein b, a melanocytic cell marker, is a melanosome-specific and proteolytically released protein.
abstract: Melanosomes are organelles specialized for the production of melanin pigment and are specifically produced by melanocytic cells. More than 150 pigmentation-related genes have been identified, including glycoprotein nonmetastatic melanoma protein b (GPNMB). A recent proteomics analysis revealed that GPNMB is localized in melanosomes, and GPNMB is a membrane-bound glycoprotein that shows high homology with a well-known melanosomal structural protein, Pmel17/gp100. In this study, we show that GPNMB is expressed in melanocytes of normal human skin, as well as in human melanoma cells. GPNMB is heavily glycosylated and is enriched in mature (stage III and IV) melanosomes in contrast to MART-1 and Pmel17, which are abundant in early (stage I and II) melanosomes. MART-1 and Pmel17 play critical roles in the maturation of early melanosomes; thus, we speculate that GPNMB might be important in the functions of late melanosomes, possibly their transport and/or transfer to keratinocytes. We also demonstrate that a secreted form of GPNMB is released by ectodomain shedding from the largely Golgi-modified form of GPNMB and that the PKC and Ca(2+) intracellular signaling pathways regulate that shedding. We conclude that GPNMB is a melanosomal protein that is released by proteolytic ectodomain shedding and might be a useful and specific histological marker of melanocytic cells.
authors.affiliation: Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-4256, USA.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Hoashi
authors.forename: Shinichi
authors.initials: S
authors.lastname: Sato
authors.forename: Yuji
authors.initials: Y
authors.lastname: Yamaguchi
authors.forename: Thierry
authors.initials: T
authors.lastname: Passeron
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Tamaki
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: Hearing
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism*; D045744:Cell Line, Tumor; D003470:Culture Media / Q000378:metabolism; D004817:Epidermis / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008544:Melanocytes / Q000378:metabolism*; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D020460:Melanosomes / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D009367:Neoplasm Staging; D055550:Protein Stability; D040901:Proteomics; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology; D058951:gp100 Melanoma Antigen
chemical_list: D014408:Biomarkers, Tumor; D003470:Culture Media; C503042:GPNMB protein, human; D008562:Membrane Glycoproteins; C548637:PMEL protein, human; D058951:gp100 Melanoma Antigen