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Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation
Published on: May 20, 2020
Systematic Identification of Oncogenic EGFR Interaction Partners
Julia Petschnigg1, Max Kotlyar2, Louise Blair1
1MRC Laboratory for Molecular Cell Biology, University College London, London, WC1E 6BT, UK.
Abstract:
The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase (TK) that-once activated upon ligand binding-leads to receptor dimerization, recruitment of protein complexes, and activation of multiple signaling cascades. The EGFR is frequently overexpressed or mutated in various cancers leading to aberrant signaling and tumor growth. Hence, identification of interaction partners that bind to mutated EGFR can help identify novel targets for drug discovery. Here, we used a systematic approach to identify novel proteins that are involved in cancerous EGFR signaling. Using a combination of high-content imaging and a mammalian membrane two-hybrid protein-protein interaction method, we identified eight novel interaction partners of EGFR, of which half strongly interacted with oncogenic, hyperactive EGFR variants. One of these, transforming acidic coiled-coil proteins (TACC) 3, stabilizes EGFR on the cell surface, which results in an increase in downstream signaling via the mitogen-activated protein kinase and AKT pathway. Depletion of TACC3 from cells using small hairpin RNA (shRNA) knockdown or small-molecule targeting reduced mitogenic signaling in non-small cell lung cancer cell lines, suggesting that targeting TACC3 has potential as a new therapeutic approach for non-small cell lung cancer.
Insights
Researchers identified new proteins interacting with cancer-linked epidermal growth factor receptor (EGFR). One protein, TACC3, stabilizes EGFR, driving cancer growth; targeting TACC3 may offer new lung cancer therapies.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase (TK) implicated in various cancers due to overexpression or mutation.
- Aberrant EGFR signaling drives tumor growth, necessitating the identification of novel interaction partners for drug discovery.
- Understanding mutated EGFR signaling pathways is crucial for developing targeted cancer therapies.
Purpose of the Study:
- To systematically identify novel proteins interacting with EGFR in cancer signaling.
- To investigate the role of identified interaction partners, particularly with oncogenic EGFR variants.
- To explore the therapeutic potential of targeting identified EGFR interaction partners in non-small cell lung cancer (NSCLC).
Main Methods:
- Utilized high-content imaging and a mammalian membrane two-hybrid protein-protein interaction assay.
- Identified and validated novel EGFR interaction partners.
- Employed small hairpin RNA (shRNA) for TACC3 depletion and small-molecule inhibitors for targeting TACC3.
Main Results:
- Eight novel EGFR interaction partners were identified.
- Half of the identified partners showed strong interaction with hyperactive EGFR variants.
- Transforming acidic coiled-coil proteins (TACC) 3 was found to stabilize cell surface EGFR, enhancing downstream signaling via MAPK and AKT pathways.
- TACC3 depletion or inhibition reduced mitogenic signaling in NSCLC cell lines.
Conclusions:
- TACC3 plays a critical role in stabilizing EGFR and promoting oncogenic signaling in NSCLC.
- Targeting TACC3 presents a promising therapeutic strategy for NSCLC treatment.
- The identified novel EGFR interactors offer potential new targets for cancer drug discovery.
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