A Mechanism for the Upregulation of EGF Receptor Levels in Glioblastomas

•tTG is upregulated in ∼70% of human glioblastomas•Increases in tTG expression and activation are associated with poor patient survival•tTG upregulates EGFR expression levels in glioblastoma cells•tTG blocks EGFR degradation by inhibiting c-Cbl-mediated EGFR ubiquitylation

SummaryTissue transglutaminase (tTG) is a GTP-binding protein/acyltransferase whose expression is upregulated in glioblastoma and associated with decreased patient survival. Here, we delineate a unique mechanism by which tTG contributes to the development of gliomas by using two glioblastoma cell lines, U87 and LN229, whose growth and survival are dependent on tTG. We show that tTG significantly enhances the signaling activity and lifespan of EGF receptors (EGFRs) in these brain cancer cells. Moreover, overexpressing tTG in T98G glioblastoma cells that normally express low levels of tTG caused a marked upregulation of EGFR expression and transforming activity. Furthermore, we show that tTG accentuates EGFR signaling by blocking c-Cbl-catalyzed EGFR ubiquitylation through the ability of tTG to bind GTP and adopt a specific conformation that enables it to interact with c-Cbl. These findings demonstrate that tTG contributes to gliomagenesis by interfering with EGFR downregulation and, thereby, promoting transformation.

Graphical AbstractFigure optionsDownload full-size imageDownload as PowerPoint slide