Spontaneous activation and signaling by overexpressed epidermal growth factor receptors in glioblastoma cells.

Overexpressed epidermal growth receptor factor receptors (EGFRs) are thought to contribute to the malignant phenotype of human glioblastomas (GBMs), but the mechanism is not well understood. We found that SKMG-3 cells, a rare GBM cell line that maintains EGFR gene amplification in vitro, produced high levels of EGFR protein. The cells also expressed the related receptors HER2/neu and HER4, but not HER3. Immunoblots and tryptic phosphopeptide maps showed that the SKMG-3 EGFRs were intact and functional and that a subset of these receptors were spontaneously autophosphorylated. EGF treatment stimulated phosphorylation of the EGFRs as well as the downstream effectors Erk, AKT1, stat3 and c-Cbl. Under minimal growth conditions, the unstimulated SKMG-3 cells contained constitutively phosphorylated Erk and AKTI but no detectable stat3 DNA-binding complexes. The EGFR kinase inhibitor PD158780 reduced the constitutive phosphorylation of the receptor and Erk but not that of AKT1. In contrast, inhibition of phosphatidylinositol-3-kinase (PI3K) blocked the constitutive phosphorylation of Erk and AKT-1 but not the EGFR. We conclude that the SKMG-3 cells represent the subset of GBMs with amplified EGFR genes that overexpress intact receptors. The results also suggest that in some GBMs, signals from overexpressed EGFRs contribute to the constitutive phosphorylation of Erk, but these signals may not required for the constitutive activation of PI3K or AKT1.

Thomas CY ，Chouinard M ，Cox M ，Parsons S ，Stallings-Mann M ，Garcia R ，Jove R ，Wharen R ... -  《INTERNATIONAL JOURNAL OF CANCER》

Sustained mitogen-activated protein kinase activation is induced by transforming erbB receptor complexes.

Wu CJ ，Qian X ，O'Rourke DM 《DNA AND CELL BIOLOGY》

Increased expression of epidermal growth factor receptor induces sequestration of extracellular signal-related kinases and selective attenuation of specific epidermal growth factor-mediated signal transduction pathways.

Habib AA ，Chun SJ ，Neel BG ，Vartanian T ... -  《MOLECULAR CANCER RESEARCH》

Resistance to small molecule inhibitors of epidermal growth factor receptor in malignant gliomas.

Li B ，Chang CM ，Yuan M ，McKenna WG ，Shu HK ... -  《CANCER RESEARCH》

Phosphorylation and nuclear exclusion of the forkhead transcription factor FKHR after epidermal growth factor treatment in human breast cancer cells.

Jackson JG ，Kreisberg JI ，Koterba AP ，Yee D ，Brattain MG ... -  《ONCOGENE》