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Bidirectional signaling between the estrogen receptor and the epidermal growth factor receptor
1Division of Endocrinology, Long Beach Veterans Affairs Medical Center, Long Beach, California 90822, USA. ellis.levin@med.va.gov
Abstract:
Interactions between the estrogen receptor (ER) and the epidermal growth factor receptor (EGFR) contribute to the biological effects of these binding protein families. EGFR stimulates DNA synthesis and gene transcription in the uterus, related in part to estrogen-independent activation of the nuclear ER. This results from signal transduction enacted by the plasma membrane tyrosine kinase growth factor receptor, leading to 1) phosphorylation and activation of the nuclear ER, and 2) phosphorylation of coregulator proteins. More recently, it has been shown that a pool of ERalpha resides in or associates with the plasma membrane as a cytoplasmic protein. These ERs utilize the membrane EGFR to rapidly signal through various kinase cascades that influence both transcriptional and nontranscriptional actions of estrogen in breast cancer cells. This is congruent with a general theme of receptor signaling, where membrane G protein-coupled receptors activate tyrosine kinase growth factor receptors (EGFR, IGF-I receptor) that subsequently signal to MAPKs and other pathways. Overall, the bidirectional cross-talk between EGFR and cellular pools of ER contributes to reproductive organ physiology and pathophysiology.
Insights
Estrogen receptor (ER) and epidermal growth factor receptor (EGFR) interactions influence reproductive organ function. EGFR signaling activates ER, impacting gene transcription and cell growth in both normal and cancerous tissues.
Area of Science:
- Endocrinology
- Molecular Biology
- Cell Signaling
Background:
- Estrogen receptor (ER) and epidermal growth factor receptor (EGFR) are key signaling proteins.
- Cross-talk between ER and EGFR influences cellular processes like DNA synthesis and gene transcription.
Purpose of the Study:
- To elucidate the signaling mechanisms and biological consequences of ER-EGFR interactions.
- To investigate the role of membrane-associated ERalpha in EGFR-mediated signaling.
Main Methods:
- Investigated signal transduction pathways initiated by EGFR.
- Examined the phosphorylation and activation of nuclear and membrane-associated ER.
- Analyzed the impact on transcriptional and non-transcriptional cellular actions.
Main Results:
- EGFR stimulates estrogen-independent activation of nuclear ER via phosphorylation.
- A pool of ERalpha is localized at the plasma membrane, interacting with EGFR.
- EGFR-ER signaling influences kinase cascades, affecting cellular functions.
Conclusions:
- Bidirectional cross-talk between EGFR and ER is crucial for reproductive organ physiology and pathophysiology.
- Understanding these interactions provides insights into hormone-driven diseases like breast cancer.