Differential epidermal growth factor receptor signaling regulates anchorage-independent growth by modulation of the PI3K AKT pathway

• Published in: Oncogene Vol. 29; no. 8; pp. 1214 - 1226
• Main Authors: Humtsoe, J O, Kramer, R H
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 25.02.2010; Nature Publishing Group
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Analysis; Apoptosis; Biological and medical sciences; Cell Biology; Cell culture; Cell growth; Cell Movement - physiology; Cell physiology; Cell Proliferation; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cellular biology; Cellular stress response; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p27 - metabolism; Dormancy; Epidermal growth factor; Epidermal growth factor receptors; Extracellular signal-regulated kinase; Fetal Proteins - metabolism; Fundamental and applied biological sciences. Psychology; Genetic aspects; Genetics; Glycogen Synthase Kinase 3 - metabolism; Human Genetics; Internal Medicine; MAP Kinase Signaling System - physiology; Medicine; Medicine & Public Health; Microenvironments; Microtubule-Associated Proteins - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Molecular and cellular biology; Neoplasms; NF-E2-Related Factor 2 - metabolism; Nuclear Proteins - metabolism; Oncology; original-article; Phosphatidylinositol; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Physiological aspects; Proto-Oncogene Proteins c-akt - metabolism; Receptor, Epidermal Growth Factor - physiology; Signal transduction; Signal Transduction - physiology; Spheroids, Cellular - physiology; STAT3 Transcription Factor; Tumor cells; Tumor Suppressor Proteins - pharmacology; Tumors; United States; cell–cell adhesion; EGFR; PI3K/AKT; Regulation(control); cell-cell adhesion; Growth; Cell adhesion; Akt protein kinase; Carcinogenesis; Epidermal growth factor receptor
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2009.419

Tumor cells are capable of surviving loss of nutrients and anchorage in hostile microenvironments. Under these conditions, adapting to specific signaling pathways may shift the balance between growth and cellular dormancy. Here, we report a mechanism by which epidermal growth factor receptor (EGFR) differentially modulates the phosphatidylinositol 3′-kinase (PI3K)/AKT pathway in cellular stress conditions. When carcinoma cells were cultured as multicellular aggregates (MCA), cyclin D1 was induced through a serum-dependent EGFR activating pathway, triggering cell proliferation. The expression of cyclin D1 required both EGFR-mediated ERK and AKT activation. In serum-starved MCAs, EGFR activation was associated with active ERK1/2, but not AKT, and failed to induce cyclin D1. Analysis revealed that, under serum-starved conditions, EGFR-Y1086 residue was poorly autophosphorylated and this correlated with failure to phosphorylate Gab1. Accordingly, the EGFR activation failed to induce EGFR/PI3K complex formation or AKT activation, preventing cyclin D1 induction. Furthermore, we show that in serum-starved MCA, expression of constitutively active AKT re-established cyclin D1 expression and induced proliferation in an EGFR-dependent manner. Thus, modulation of the PI3K/AKT pathway by context-dependent EGFR signaling may regulate tumor cell growth and dormancy.