TY - JOUR
T1 - The ErbB4 CYT2 variant protects EGFR from ligand-induced degradation to enhance cancer cell motility
AU - Kiuchi, Tai
AU - Ortiz-Zapater, Elena
AU - Monypenny, James
AU - Matthews, Daniel R.
AU - Nguyen, Lan K.
AU - Barbeau, Jody
AU - Coban, Oana
AU - Lawler, Katherine
AU - Burford, Brian
AU - Rolfe, Daniel J.
AU - De Rinaldis, Emanuele
AU - Dafou, Dimitra
AU - Simpson, Michael A.
AU - Woodman, Natalie
AU - Pinder, Sarah
AU - Gillett, Cheryl E.
AU - Devauges, Viviane
AU - Poland, Simon P.
AU - Fruhwirth, Gilbert
AU - Marra, Pierfrancesco
AU - Boersma, Ykelien L.
AU - Plückthun, Andreas
AU - Gullick, William J.
AU - Yarden, Yosef
AU - Santis, George
AU - Winn, Martyn
AU - Kholodenko, Boris N.
AU - Martin-Fernandez, Marisa L.
AU - Parker, Peter
AU - Tutt, Andrew
AU - Ameer-Beg, Simon M.
AU - Ng, Tony
N1 - Copyright:
Copyright 2014 Elsevier B.V., All rights reserved.
PY - 2014/8/19
Y1 - 2014/8/19
N2 - The epidermal growth factor receptor (EGFR) is a member of the ErbB family that can promote the migration and proliferation of breast cancer cells. Therapies that target EGFR can promote the dimerization of EGFR with other ErbB receptors, which is associated with the development of drug resistance. Understanding how interactions among ErbB receptors alter EGFR biology could provide avenues for improving cancer therapy. We found that EGFR interacted directly with the CYT1 and CYT2 variants of ErbB4 and the membrane-anchored intracellular domain (mICD). The CYT2 variant, but not the CYT1 variant, protected EGFR from ligand-induced degradation by competing with EGFR for binding to a complex containing the E3 ubiquitin ligase c-Cbl and the adaptor Grb2. Cultured breast cancer cells overexpressing both EGFR and ErbB4 CYT2 mICD exhibited increased migration. With molecular modeling, we identified residues involved in stabilizing the EGFR dimer. Mutation of these residues in the dimer interface destabilized the complex in cells and abrogated growth factor-stimulated cell migration. An exon array analysis of 155 breast tumors revealed that the relative mRNA abundance of the ErbB4 CYT2 variant was increased in ER+ HER2- breast cancer patients, suggesting that our findings could be clinically relevant. We propose a mechanism whereby competition for binding to c-Cbl in an ErbB signaling heterodimer promotes migration in response to a growth factor gradient.
AB - The epidermal growth factor receptor (EGFR) is a member of the ErbB family that can promote the migration and proliferation of breast cancer cells. Therapies that target EGFR can promote the dimerization of EGFR with other ErbB receptors, which is associated with the development of drug resistance. Understanding how interactions among ErbB receptors alter EGFR biology could provide avenues for improving cancer therapy. We found that EGFR interacted directly with the CYT1 and CYT2 variants of ErbB4 and the membrane-anchored intracellular domain (mICD). The CYT2 variant, but not the CYT1 variant, protected EGFR from ligand-induced degradation by competing with EGFR for binding to a complex containing the E3 ubiquitin ligase c-Cbl and the adaptor Grb2. Cultured breast cancer cells overexpressing both EGFR and ErbB4 CYT2 mICD exhibited increased migration. With molecular modeling, we identified residues involved in stabilizing the EGFR dimer. Mutation of these residues in the dimer interface destabilized the complex in cells and abrogated growth factor-stimulated cell migration. An exon array analysis of 155 breast tumors revealed that the relative mRNA abundance of the ErbB4 CYT2 variant was increased in ER+ HER2- breast cancer patients, suggesting that our findings could be clinically relevant. We propose a mechanism whereby competition for binding to c-Cbl in an ErbB signaling heterodimer promotes migration in response to a growth factor gradient.
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U2 - 10.1126/scisignal.2005157
DO - 10.1126/scisignal.2005157
M3 - Article
AN - SCOPUS:84906829733
VL - 7
JO - Science's STKE : signal transduction knowledge environment
JF - Science's STKE : signal transduction knowledge environment
SN - 1937-9145
IS - 339
M1 - ra78
ER -