Src family kinases mediate epidermal growth factor receptor signaling from lipid rafts in breast cancer cells
- 15 October 2011
- journal article
- Published by Taylor & Francis Ltd in Cancer Biology & Therapy
- Vol. 12 (8), 718-726
- https://doi.org/10.4161/cbt.12.8.16907
Abstract
Activation of the epidermal growth factor receptor (EGFR) regulates cellular proliferation, survival, and migration of breast cancer cells. In particular, EGFR recruits signaling proteins to the cell membrane leading to their phosphorylation and activation. However, EGFR also localizes to other cellular structures, including endosomes, mitochondrion, and nuclei. Recently, we demonstrated that lipid raft localization of EGFR in triple-negative breast cancer cell lines promotes EGFR protein-dependent, EGFR kinase-independent activation of Akt. Here, we further define the mechanism by which lipid rafts regulate EGFR signaling to Akt. Specifically, we show that the non-receptor tyrosine kinase c-Src co-localizes and co-associates with EGFR and lipid rafts. Breast cancer cells resistant to treatment with EGFR inhibitors, were also resistant to treatment with Src family kinase (SFK) inhibitors; however, the combination of EGFR and SFK inhibitors synergistically decreases cell viability. We found that this decrease in cell viability observed with EGFR and SFK inhibitor co-treatment correlates with loss of Akt phosphorylation. In addition, we found that in breast cancer cell lines with EGFR and c-Src co-localized to lipid rafts, phospho-inositide 3 kinase (PI3K) was also associated with lipid rafts. Together, the data herein suggest that lipid rafts provide a platform for the interaction of EGFR, c-Src, and PI3K, leading to activation of cellular survival signaling in breast cancer cells.Keywords
This publication has 55 references indexed in Scilit:
- Lipid raft localization of EGFR alters the response of cancer cells to the EGFR tyrosine kinase inhibitor gefitinibJournal of Cellular Physiology, 2010
- EGFR/Met association regulates EGFR TKI resistance in breast cancerJournal of Molecular Signaling, 2010
- Phase I/II Study of the Src Inhibitor Dasatinib in Combination With Erlotinib in Advanced Non–Small-Cell Lung CancerJournal of Clinical Oncology, 2010
- Improved Response by Co-targeting EGFR/EGFRvIII and Src Family Kinases in Human Cancer CellsCancer Investigation, 2009
- c-Src trafficking and co-localization with the EGF receptor promotes EGF ligand-independent EGF receptor activation and signalingCellular Signalling, 2008
- Combined Inhibition of c-Src and Epidermal Growth Factor Receptor Abrogates Growth and Invasion of Head and Neck Squamous Cell CarcinomaClinical Cancer Research, 2008
- An Allosteric Mechanism for Activation of the Kinase Domain of Epidermal Growth Factor ReceptorCell, 2006
- Discovery of N-(2-Chloro-6-methyl- phenyl)-2-(6-(4-(2-hydroxyethyl)- piperazin-1-yl)-2-methylpyrimidin-4- ylamino)thiazole-5-carboxamide (BMS-354825), a Dual Src/Abl Kinase Inhibitor with Potent Antitumor Activity in Preclinical AssaysJournal of Medicinal Chemistry, 2004
- A transferrin-like GPI-linked iron-binding protein in detergent-insoluble noncaveolar microdomains at the apical surface of fetal intestinal epithelial cells.The Journal of cell biology, 1995
- Site-Specific Association of c-SRC with Epidermal Growth Factor Receptor in A431 CellsBiochemical and Biophysical Research Communications, 1995