A human brain tumor-derived PDGFR- α deletion mutant is transforming

摘要: Aberrant receptor tyrosine kinase signaling plays an important role in the molecular pathogenesis of brain tumors. We have been studying a previously identified human glioblastoma-derived PDGFR-α mutant that has in-frame deletion extracellular domain, causing loss exons 8 and 9 (PDGFR-αΔ8,9). In primary tumor, this was shown to be amplified overexpressed. The purpose study determine expression, activity, localization, transformation properties mutant. absence serum, or PDGF-AA, PDGFR-αΔ8,9 phosphorylated on residues, indicating ligand-independent autoactivation. Localization by staining cell surface biotinylation studies revealed expression predominantly cytoplasm, with very little present surface. To if oncogenic, we transfected wild-type receptors into Rat1 cells performed analyses growth, vitro transformation, subcutaneous growth nude mouse. PDGFR-αΔ8,9-expressing displayed enhanced survival low formed foci monolayer cultures. were also tumorigenic when injected subcutaneously mice. Expression associated increased c-Jun phosphorylation PDGF ligand, demonstrating is altered intracellular signaling. These data demonstrate transforming, it first demonstration naturally occurring tumor-derived oncogenic properties.