Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-4256, USA.
FASEB J. 2010 May;24(5):1616-29. doi: 10.1096/fj.09-151019. Epub 2010 Jan 7.
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.
黑素体是专门用于生产黑色素色素的细胞器，并且是由黑素细胞特异性产生的。已经鉴定出超过 150 个与色素沉着相关的基因，包括糖蛋白非转移性黑色素瘤蛋白 b (GPNMB)。最近的蛋白质组学分析表明，GPNMB 定位于黑素体中，GPNMB 是一种膜结合糖蛋白，与众所周知的黑素体结构蛋白 Pmel17/gp100 具有高度同源性。在这项研究中，我们表明 GPNMB 在正常人皮肤的黑素细胞以及人类黑色素瘤细胞中表达。GPNMB 高度糖基化，并且在成熟（III 期和 IV 期）黑素体中富集，而 MART-1 和 Pmel17 在早期（I 期和 II 期）黑素体中丰富。MART-1 和 Pmel17 在早期黑素体的成熟中起着关键作用；因此，我们推测 GPNMB 可能在晚期黑素体的功能中很重要，可能在它们的运输和/或向角质形成细胞的转移中很重要。我们还证明了 GPNMB 的一种分泌形式通过 GPNMB 的主要高尔基修饰形式的蛋白水解细胞外结构域脱落而释放，并且蛋白激酶 C 和 Ca(2+) 细胞内信号通路调节该脱落。我们得出结论，GPNMB 是一种黑素体蛋白，通过蛋白水解细胞外结构域脱落而释放，可能是黑素细胞的有用且特异性的组织学标志物。
