title: A mechanism for the upregulation of EGF receptor levels in glioblastomas.
abstract: Tissue 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.
authors.affiliation: Department of Molecular Medicine, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Jingwen
authors.initials: J
authors.lastname: Zhang
authors.forename: Marc A
authors.initials: MA
authors.lastname: Antonyak
authors.forename: Garima
authors.initials: G
authors.lastname: Singh
authors.forename: Richard A
authors.initials: RA
authors.lastname: Cerione
mesh_terms: D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D066246:ErbB Receptors