Etude des mutations K385I/L du récepteur PDGFRα dans les tumeurs glioneuronales myxoïdes

Details

Supervisors

Demoulin, Jean-Baptiste

Faculty

Faculté de pharmacie et des sciences biomédicales

Degree label

Master [120] en sciences biomédicales, à finalité approfondie

Abstract

enThe tyrosine kinase PDGFRα receptor is required for cell proliferation, migration and survival. When PDGF binds to the receptor, it dimerizes and autophosphorylates to activate intracellular signaling cascades including the MAP kinase pathway, the phosphatidylinositol-3 kinase pathway, the phospholipase C-γ pathway and the STAT pathway. The receptor is involved in various diseases and cancers when mutated or overexpressed. Recently, the K385I/L mutation of the PDGFRα receptor has been recurrently identified in patients with myxoid glioneuronal tumors (MGNT) in the central nervous system. The goal of this project was to characterize the K385I/L mutation of the PDGFRα receptor. We transfected the mutated receptor gene into glioblastoma cell lines. After confirming receptors expression by western blot, we analyzed the activity of the mutated PDGFRα. The results suggested that the change of lysine to leucine/isoleucine at position 385 causes a constitutive activation of several signaling pathways, i.e. independently of the presence of ligand. A fibroblast transformation assay confirmed the oncogenic potential of the K385I/L mutation. The mutation is located in the fourth immunoglobulin domain of the extracellular part of the receptor, which is involved in the dimerization of the receptor. Crosslinking and co-immunoprecipitation experiments showed that activation occurs through constitutive dimerization of the PDGFRα receptor. In conclusion, our results validated the PDGFRα K385I/L mutation as an oncogene through a constitutive receptor dimerization.