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

Abstract

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 f20% 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-Adependent 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.

Quantitative Proteomic Analysis Reveals Effects of Epidermal Growth Factor Receptor (EGFR) on Invasion-promoting Proteins Secreted by Glioblastoma Cells

“…The fact that we can see increased expression of invasion-promoting proteins in ϩEGFRvIII cells correlates well with the observation Table S1. that EGFRvIII-expressing tumors display higher invasive and proliferative behavior (60). The SRM analysis showed that wtEGFR protein was present at high levels in the ϩEGFR and ϩPE cell lines, but was at nondetectable levels in all other cell lines, including ϩEGFRvIII.…”

A Novel Predictor of Cancer Malignancy: Up-regulation of Myristoylated Alanine-Rich C Kinase Substrate Phosphorylation in Lung Cancer

“…Inhibition of MARCKS activity not only reduces airway mucus hypersecretion both in vitro and in vivo (3,5), but also represses inflammatory leukocyte migration and degranulation (6, 7). There have been limited studies on MARCKS in cancer metastasis, but the results have been conflicting (8)(9)(10)(11)(12)(13). This is because MARCKS expression is ubiquitous in various normal and tumor tissues.…”

Myristoylated Alanine‐Rich Protein Kinase Substrate (MARCKS) Regulates Small GTPase Rac1 and Cdc42 Activity and Is a Critical Mediator of Vascular Smooth Muscle Cell Migration in Intimal Hyperplasia Formation

“…MARCKS is a well‐established regulator of migration in multiple cell types. Dysregulation of MARCKS is closely associated with metastasis in a wide range of cancers and is an indicator of poor prognosis 19, 20. MARCKS increases cell motility through the protein kinase B pathway in fibroblasts21 and glial cells 22.…”