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Epidermal Growth Factor Receptor Variant III–Induced Glioma Invasion Is Mediated through Myristoylated Alanine-Rich Protein Kinase C Substrate Overexpression

¹ Arthur & Sonia Labatt Brain Tumor Center and ² Program in Molecular Structure and Function, Hospital for Sick Children; ³ Departments of Pathology and Laboratory Medicine and Pathobiology, University Health Network, ⁴ Division of Neurosurgery, Western Hospital, and ⁵ McLaughlin Centre for Molecular Medicine and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada; and ⁶ Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida

Requests for reprints: Abhijit Guha, 4W-446, 399 Bathurst Street, Toronto, Ontario, Canada M5T-2S8. Phone: 416-603-5740; Fax: 416-603-5298; E-mail: Abhijit.Guha{at}uhn.on.ca.

Key Words: GBM • MARCKS • EGFRvIII • Invasion • PKC

Glioblastoma multiforme (GBM) is the most common and most malignant adult brain tumor. A characteristic of GBM is their highly invasive nature, making complete surgical resection impossible. The most common gain-of-function alteration in GBM is amplification, overexpression, and mutations of the epidermal growth factor receptor (EGFR). The constitutively activated mutant EGFR variant III (EGFRvIII), found in 20% of GBM, confers proliferative and invasive advantage. The signaling cascades downstream of aberrant EGFR activation contributing to the invasive phenotype are not completely understood. Here, we show myristoylated alanine-rich protein kinase C substrate (MARCKS), previously implicated in cell adhesion and motility, contributes to EGFR-mediated invasion of human GBM cells. EGFRvIII-expressing or EGF-stimulated human GBM cells increased expression, phosphorylation, and cytosolic translocation of MARCKS in a protein kinase C-–dependent manner. Down-regulation of MARCKS expression with small interfering RNA in GBM cells expressing EGFRvIII led to decreased cell adhesion, spreading, and invasion. Elucidation of mechanisms that promote EGFRvIII-mediated tumorigenesis in GBM, such as MARCKS, provides additional understanding and potential biological targets against this currently terminal human cancer. [Cancer Res 2009;69(19):7548–56]