title: The ErbB4 CYT2 variant protects EGFR from ligand-induced degradation to enhance cancer cell motility.
abstract: 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.
authors.affiliation: Richard Dimbleby Department of Cancer Research, Randall Division of Cell and Molecular Biophysics, King's College London, Guy's Medical School Campus, London SE1 1UL, UK. Division of Cancer Studies, King's College London, London SE1 1UL, UK. Breakthrough Breast Cancer Research Unit, Research Oncology, King's College London, Guy's Hospital, London SE1 9RT, UK.
authors.forename: Tai
authors.initials: T
authors.lastname: Kiuchi
authors.affiliation: Department of Asthma, Allergy and Respiratory Science, King's College London, Guy's Hospital, London SE1 9RT, UK.
authors.forename: Elena
authors.initials: E
authors.lastname: Ortiz-Zapater
authors.affiliation: Richard Dimbleby Department of Cancer Research, Randall Division of Cell and Molecular Biophysics, King's College London, Guy's Medical School Campus, London SE1 1UL, UK. Division of Cancer Studies, King's College London, London SE1 1UL, UK. Breakthrough Breast Cancer Research Unit, Research Oncology, King's College London, Guy's Hospital, London SE1 9RT, UK.
authors.forename: James
authors.initials: J
authors.lastname: Monypenny
authors.affiliation: Richard Dimbleby Department of Cancer Research, Randall Division of Cell and Molecular Biophysics, King's College London, Guy's Medical School Campus, London SE1 1UL, UK. Division of Cancer Studies, King's College London, London SE1 1UL, UK.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Matthews
authors.affiliation: Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Lan K
authors.initials: LK
authors.lastname: Nguyen
authors.affiliation: Richard Dimbleby Department of Cancer Research, Randall Division of Cell and Molecular Biophysics, King's College London, Guy's Medical School Campus, London SE1 1UL, UK. Division of Cancer Studies, King's College London, London SE1 1UL, UK.
authors.forename: Jody
authors.initials: J
authors.lastname: Barbeau
authors.affiliation: Richard Dimbleby Department of Cancer Research, Randall Division of Cell and Molecular Biophysics, King's College London, Guy's Medical School Campus, London SE1 1UL, UK. Division of Cancer Studies, King's College London, London SE1 1UL, UK.
authors.forename: Oana
authors.initials: O
authors.lastname: Coban
authors.affiliation: Richard Dimbleby Department of Cancer Research, Randall Division of Cell and Molecular Biophysics, King's College London, Guy's Medical School Campus, London SE1 1UL, UK. Division of Cancer Studies, King's College London, London SE1 1UL, UK.
authors.forename: Katherine
authors.initials: K
authors.lastname: Lawler
authors.affiliation: Breakthrough Breast Cancer Research Unit, Research Oncology, King's College London, Guy's Hospital, London SE1 9RT, UK.
authors.forename: Brian
authors.initials: B
authors.lastname: Burford
authors.affiliation: Central Laser Facility, Rutherford Appleton Laboratory, Science and Technology Facilities Council, Research Complex at Harwell, Didcot OX11 0QX, UK.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rolfe
authors.affiliation: Breakthrough Breast Cancer Research Unit, Research Oncology, King's College London, Guy's Hospital, London SE1 9RT, UK.
authors.forename: Emanuele
authors.initials: E
authors.lastname: de Rinaldis
authors.affiliation: Genetics and Molecular Medicine, King's College London, Guy's Hospital, London SE1 9RT, UK.
authors.forename: Dimitra
authors.initials: D
authors.lastname: Dafou
authors.affiliation: Genetics and Molecular Medicine, King's College London, Guy's Hospital, London SE1 9RT, UK.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Simpson
authors.affiliation: Guy's and St Thomas' Breast Tissue and Data Bank, King's College London, Guy's Hospital, London SE1 9RT, UK. Research Oncology, Division of Cancer Studies, King's College London, Guy's Hospital, London SE1 9RT, UK.
authors.forename: Natalie
authors.initials: N
authors.lastname: Woodman
authors.affiliation: Guy's and St Thomas' Breast Tissue and Data Bank, King's College London, Guy's Hospital, London SE1 9RT, UK. Research Oncology, Division of Cancer Studies, King's College London, Guy's Hospital, London SE1 9RT, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Pinder
authors.affiliation: Guy's and St Thomas' Breast Tissue and Data Bank, King's College London, Guy's Hospital, London SE1 9RT, UK. Research Oncology, Division of Cancer Studies, King's College London, Guy's Hospital, London SE1 9RT, UK.
authors.forename: Cheryl E
authors.initials: CE
authors.lastname: Gillett
authors.affiliation: Richard Dimbleby Department of Cancer Research, Randall Division of Cell and Molecular Biophysics, King's College London, Guy's Medical School Campus, London SE1 1UL, UK. Division of Cancer Studies, King's College London, London SE1 1UL, UK.
authors.forename: Viviane
authors.initials: V
authors.lastname: Devauges
authors.affiliation: Richard Dimbleby Department of Cancer Research, Randall Division of Cell and Molecular Biophysics, King's College London, Guy's Medical School Campus, London SE1 1UL, UK. Division of Cancer Studies, King's College London, London SE1 1UL, UK.
authors.forename: Simon P
authors.initials: SP
authors.lastname: Poland
authors.affiliation: Richard Dimbleby Department of Cancer Research, Randall Division of Cell and Molecular Biophysics, King's College London, Guy's Medical School Campus, London SE1 1UL, UK. Division of Cancer Studies, King's College London, London SE1 1UL, UK.
authors.forename: Gilbert
authors.initials: G
authors.lastname: Fruhwirth
authors.affiliation: Breakthrough Breast Cancer Research Unit, Research Oncology, King's College London, Guy's Hospital, London SE1 9RT, UK.
authors.forename: Pierfrancesco
authors.initials: P
authors.lastname: Marra
authors.affiliation: Department of Biochemistry, University of Zurich, 190, 8057 Zurich, Switzerland.
authors.forename: Ykelien L
authors.initials: YL
authors.lastname: Boersma
authors.affiliation: Department of Biochemistry, University of Zurich, 190, 8057 Zurich, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Plückthun
authors.affiliation: Department of Biosciences, University of Kent, Canterbury, Kent CT2 7NJ, UK.
authors.forename: William J
authors.initials: WJ
authors.lastname: Gullick
authors.affiliation: Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Yosef
authors.initials: Y
authors.lastname: Yarden
authors.affiliation: Department of Asthma, Allergy and Respiratory Science, King's College London, Guy's Hospital, London SE1 9RT, UK.
authors.forename: George
authors.initials: G
authors.lastname: Santis
authors.affiliation: Computational Science and Engineering Department, Daresbury Laboratory, Science and Technology Facilities Council, Research Complex at Warrington, Warrington WA4 4AD, UK.
authors.forename: Martyn
authors.initials: M
authors.lastname: Winn
authors.affiliation: Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Boris N
authors.initials: BN
authors.lastname: Kholodenko
authors.affiliation: Central Laser Facility, Rutherford Appleton Laboratory, Science and Technology Facilities Council, Research Complex at Harwell, Didcot OX11 0QX, UK.
authors.forename: Marisa L
authors.initials: ML
authors.lastname: Martin-Fernandez
authors.affiliation: Division of Cancer Studies, King's College London, London SE1 1UL, UK. Protein Phosphorylation Laboratory, Cancer Research UK, London Research Institute, Lincoln's Inn Fields, London WC2A 3PX, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Parker
authors.affiliation: Breakthrough Breast Cancer Research Unit, Research Oncology, King's College London, Guy's Hospital, London SE1 9RT, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Tutt
authors.affiliation: Richard Dimbleby Department of Cancer Research, Randall Division of Cell and Molecular Biophysics, King's College London, Guy's Medical School Campus, London SE1 1UL, UK. Division of Cancer Studies, King's College London, London SE1 1UL, UK. simon.ameer-beg@kcl.ac.uk tony.ng@kcl.ac.uk.
authors.forename: Simon M
authors.initials: SM
authors.lastname: Ameer-Beg
authors.affiliation: Richard Dimbleby Department of Cancer Research, Randall Division of Cell and Molecular Biophysics, King's College London, Guy's Medical School Campus, London SE1 1UL, UK. Division of Cancer Studies, King's College London, London SE1 1UL, UK. Breakthrough Breast Cancer Research Unit, Research Oncology, King's College London, Guy's Hospital, London SE1 9RT, UK. UCL Cancer Institute, Paul O'Gorman Building, University College London, London WC1E 6BT, UK. simon.ameer-beg@kcl.ac.uk tony.ng@kcl.ac.uk.
authors.forename: Tony
authors.initials: T
authors.lastname: Ng
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D051380:GRB2 Adaptor Protein / Q000235:genetics / Q000378:metabolism; D006801:Humans; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000235:genetics; D059748:Proteolysis; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics / Q000378:metabolism; D066247:Receptor, ErbB-4 / Q000235:genetics / Q000378:metabolism*
chemical_list: D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D050721:Proto-Oncogene Proteins c-cbl; C512478:EGFR protein, human; C587689:ERBB4 protein, human; D066246:ErbB Receptors; D066247:Receptor, ErbB-4; C067419:CBL protein, human