Glycoprotein non-metastatic melanoma protein B functions with growth factor signaling to induce tumorigenesis through its serine phosphorylation

Cancer Sci. 2021 Oct;112(10):4187-4197. doi: 10.1111/cas.15090. Epub 2021 Aug 10.


Breast cancer is the most common cancer among women. Glycoprotein non-metastatic melanoma protein B (GPNMB), a type I transmembrane protein that is highly expressed in many cancers, including breast cancer, has been shown to be a prognostic factor. We previously reported that GPNMB overexpression confers tumorigenic potential, as evidenced by invasive tumor growth in vivo, sphere formation, and cellular migration and invasion to non-tumorigenic mammary epithelial cells. In this study, we focused on the serine (S) residue in the intracellular domain of GPNMB (S530 in human isoform b and S546 in mouse), which is predicted to be a phosphorylation site. To investigate the roles of this serine residue, we made an antibody specific for S530-phosphorylated human GPNMB and a point mutant in which S530 is replaced by an alanine (A) residue, GPNMB(SA). Established GPNMB(SA) overexpressing cells showed a significant reduction in sphere formation in vitro and tumor growth in vivo as a result of decreased stemness-related gene expression compared to that in GPNMB(WT)-expressing cells. In addition, GPNMB(SA) impaired GPNMB-mediated cellular migration. Furthermore, we found that tyrosine kinase receptor signaling triggered by epidermal growth factor or fibroblast growth factor 2 induces the serine phosphorylation of GPNMB through activation of downstream oncoproteins RAS and RAF.

Keywords: GPNMB; breast cancer; cancer stem cell; sphere formation; tumorigenesis.

MeSH terms

  • Animals
  • Antibody Specificity
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Epidermal Growth Factor / metabolism
  • Female
  • Fibroblast Growth Factor 2 / metabolism
  • Humans
  • MCF-7 Cells
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / immunology
  • Membrane Glycoproteins / physiology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Phosphorylation
  • Point Mutation
  • Protein Isoforms / genetics
  • Protein Isoforms / immunology
  • Protein Isoforms / metabolism
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Serine / metabolism*
  • Signal Transduction
  • Spheroids, Cellular / metabolism
  • Spheroids, Cellular / pathology
  • raf Kinases / metabolism
  • ras Proteins / metabolism


  • GPNMB protein, human
  • Membrane Glycoproteins
  • Protein Isoforms
  • Fibroblast Growth Factor 2
  • Serine
  • Epidermal Growth Factor
  • Receptor Protein-Tyrosine Kinases
  • raf Kinases
  • ras Proteins