Glycoprotein nonmetastatic melanoma protein B extracellular fragment shows neuroprotective effects and activates the PI3K/Akt and MEK/ERK pathways via the Na+/K+-ATPase

Glycoprotein nonmetastatic melanoma protein B (GPNMB) is a type I transmembrane protein and is also known as osteoactivin, dendritic cell-heparin integrin ligand (DC-HIL), and hematopoietic growth factor inducible neurokinin-1 type1,2,3. GPNMB is composed of three domains, including a long extracellular domain (ECD), a single transmembrane domain, and a relatively short cytoplasmic tail4. The ECD has an arginine-glycine-aspartic acid (RGD) motif that is required for the GPNMB adhesive5,6 and a polycystic kidney disease (PKD) domain whose function in GPNMB is unidentified7. GPNMB was initially cloned from poorly metastatic melanoma cells as a regulator of tumor growth8. GPNMB is important for the invasion and metastasis of several cancers, such as breast cancer9, colorectal cancer10, hepatocellular carcinoma, and cutaneous melanoma11. In addition, GPNMB plays diverse roles in normal cells, such as T-cell activation and promoting the specialization of osteoclasts and osteoblasts12,13. Moreover, we have discovered that high GPNMB protein levels were observed in the cerebrospinal fluid (CSF), sera, and spinal cords of human patients with amyotrophic lateral sclerosis (ALS)14. A number of types I transmembrane proteins are activated after cleavage into extracellular and intracellular fragments by a disintegrin and metalloproteases (ADAMs) or γ-secretase15. GPNMB is also cleaved by ADAM10, resulting in activation16. The extracellular fragment of GPNMB enhances ERK phosphorylation along with upregulating matrix metalloproteinase-3 (MMP-3) expression and induces endothelial cell migration17. We reported that GPNMB was cleaved and secreted extracellularly, and the extracellular fragment of GPNMB had protective effects against mutant superoxide dismutase 1 (SOD1)-induced neurotoxicity via the activation of the phosphoinositide-3-kinase (PI3K)/Akt and MEK/ERK pathways14. Therefore, we hypothesized that the extracellular fragment of GPNMB binds a receptor or proteins on the plasma membrane, and then activates the PI3K/Akt and MEK/ERK pathways. Here, we have identified the Na+/K+-ATPase as a receptor for the extracellular fragment of GPNMB that mediates activation of cellular signaling pathways and subsequent neuroprotective effects.