Journal
JOURNAL OF MOLECULAR BIOLOGY
Volume 429, Issue 2, Pages 280-294Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2016.12.006
Keywords
two-hybrid screening; protein-protein interaction; EGFR; non-small cell lung cancer; oncogenic signaling
Categories
Funding
- UK Medical Research Council
- BBSRC [BB/JO/5881/1]
- Deutsche Forschungsgemeinschaft [Ke904/2-1]
- Ontario Genomics Institute
- Canadian Cystic Fibrosis Foundation
- Canadian Cancer Society
- Pancreatic Cancer Canada
- University Health Network
- Ontario Research Fund [GL2-01-030]
- Canada Research Chair Programs
- EC-Marie Curie International Incoming Fellowship [FP7-PEOPLE-2013-IIF]
- Medical Research Council [MC_EX_G0800785, MC_U12266B, MC_CF12266] Funding Source: researchfish
- MRC [MC_EX_G0800785] Funding Source: UKRI
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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. (C) 2016 The Authors. Published by Elsevier Ltd.
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