Loss of VPS4B function promotes tumorigenesis in osteosarcoma by altering the endosomal degradative pathway and leading to accumulation of activated EGFR

M. Mogass, C. Alander, M.F. Hansen
University of Connecticut Health Center, US

Keywords: osteosarcoma, quantum dots, VPS4B, endosome, EGFR

Summary:

Receptor-mediated endocytosis is a critical step in growth control and development. Under ordinary conditions, receptors such as EGFR are activated by binding to ligand on the cell surface and then rapidly internalized to the endosomes at which point they are either recycled or degraded thus preventing sustained stimulation. VPS4B, a member of the family of AAA ATPases, is required for regulation of growth factor receptors via the endosome-mediated protein degradation pathway. VPS4B interacts with the ESCRT-III complex to dissociate bound and ubiquitinated growth factor receptors and to promote maturation of the early endosomes. Mutations in VPS4B that interfere with endosomal sorting could promote tumorigenesis by inhibiting both recycling of the activated receptors to the plasma membrane and degradation of the receptors via transport to the lysosomes resulting in accumulation of activated receptor-ligand complexes within the endosome. We have used quantum dots conjugated to EGF together with siRNA-mediated down regulation of VPS4B to study the dynamics of endocytic trafficking in normal and osteosarcoma tumor cells and to show the effect of loss of VPS4B on accumulation of activated EGFR-EGF complexes within endosomes and to demonstrate that loss of VPS4B can act as a tumorigenic event in osteosarcoma.