The ErbB4 CYT2 variant protects EGFR from ligand-induced degradation to enhance cancer cell motility

Tai Kiuchi; Elena Ortiz-Zapater; James Monypenny; Daniel R Matthews; Lan K Nguyen; Jody Barbeau; Oana Coban; Katherine Lawler; Brian Burford; Daniel J Rolfe; Emanuele de Rinaldis; Dimitra Dafou; Michael A Simpson; Natalie Woodman; Sarah Pinder; Cheryl E Gillett; Viviane Devauges; Simon P Poland; Gilbert Fruhwirth; Pierfrancesco Marra; Ykelien L Boersma; Andreas Plückthun; William J Gullick; Yosef Yarden; George Santis; Martyn Winn; Boris N Kholodenko; Marisa L Martin-Fernandez; Peter Parker; Andrew Tutt; Simon M Ameer-Beg; Tony Ng

doi:10.1126/scisignal.2005157

The ErbB4 CYT2 variant protects EGFR from ligand-induced degradation to enhance cancer cell motility

Tai Kiuchi, Elena Ortiz-Zapater, James Monypenny, Daniel R Matthews, Lan K Nguyen, Jody Barbeau, Oana Coban, Katherine Lawler, Brian Burford, Daniel J Rolfe, Emanuele de Rinaldis, Dimitra Dafou, Michael A Simpson, Natalie Woodman, Sarah Pinder, Cheryl E Gillett, Viviane Devauges, Simon P Poland, Gilbert Fruhwirth, Pierfrancesco MarraYkelien L Boersma, Andreas Plückthun, William J Gullick, Yosef Yarden, George Santis, Martyn Winn, Boris N Kholodenko, Marisa L Martin-Fernandez, Peter Parker, Andrew Tutt, Simon M Ameer-Beg, Tony Ng

Research output: Contribution to journal › Article › peer-review

32 Citations (Scopus)

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.

Original language	English
Article number	ra78
Number of pages	15
Journal	Science Signaling
Volume	7
Issue number	339
Early online date	19 Aug 2014
DOIs	https://doi.org/10.1126/scisignal.2005157
Publication status	Published - 19 Aug 2014

Keywords

Breast Neoplasms
Cell Line, Tumor
Cell Movement
Drug Resistance, Neoplasm
Female
GRB2 Adaptor Protein
Humans
Protein Structure, Tertiary
Protein Transport
Proteolysis
Proto-Oncogene Proteins c-cbl
Receptor, Epidermal Growth Factor
Receptor, ErbB-4

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1126/scisignal.2005157

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Kiuchi, T., Ortiz-Zapater, E., Monypenny, J., Matthews, D. R., Nguyen, L. K., Barbeau, J., Coban, O., Lawler, K., Burford, B., Rolfe, D. J., de Rinaldis, E., Dafou, D., Simpson, M. A., Woodman, N., Pinder, S., Gillett, C. E., Devauges, V., Poland, S. P., Fruhwirth, G., ... Ng, T. (2014). The ErbB4 CYT2 variant protects EGFR from ligand-induced degradation to enhance cancer cell motility. Science Signaling, 7(339), Article ra78. https://doi.org/10.1126/scisignal.2005157

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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.",

keywords = "Breast Neoplasms, Cell Line, Tumor, Cell Movement, Drug Resistance, Neoplasm, Female, GRB2 Adaptor Protein, Humans, Protein Structure, Tertiary, Protein Transport, Proteolysis, Proto-Oncogene Proteins c-cbl, Receptor, Epidermal Growth Factor, Receptor, ErbB-4",

author = "Tai Kiuchi and Elena Ortiz-Zapater and James Monypenny and Matthews, {Daniel R} and Nguyen, {Lan K} and Jody Barbeau and Oana Coban and Katherine Lawler and Brian Burford and Rolfe, {Daniel J} and {de Rinaldis}, Emanuele and Dimitra Dafou and Simpson, {Michael A} and Natalie Woodman and Sarah Pinder and Gillett, {Cheryl E} and Viviane Devauges and Poland, {Simon P} and Gilbert Fruhwirth and Pierfrancesco Marra and Boersma, {Ykelien L} and Andreas Pl{\"u}ckthun and Gullick, {William J} and Yosef Yarden and George Santis and Martyn Winn and Kholodenko, {Boris N} and Martin-Fernandez, {Marisa L} and Peter Parker and Andrew Tutt and Ameer-Beg, {Simon M} and Tony Ng",

note = "Copyright {\textcopyright} 2014, American Association for the Advancement of Science.",

year = "2014",

month = aug,

day = "19",

doi = "10.1126/scisignal.2005157",

language = "English",

volume = "7",

journal = "Science Signaling",

issn = "1945-0877",

publisher = "American Association for the Advancement of Science",

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Kiuchi, T , Ortiz-Zapater, E , Monypenny, J , Matthews, DR, Nguyen, LK, Barbeau, J , Coban, O , Lawler, K , Burford, B, Rolfe, DJ, de Rinaldis, E, Dafou, D, Simpson, MA, Woodman, N, Pinder, S , Gillett, CE , Devauges, V , Poland, SP, Fruhwirth, G, Marra, P, Boersma, YL, Plückthun, A, Gullick, WJ, Yarden, Y, Santis, G, Winn, M, Kholodenko, BN, Martin-Fernandez, ML, Parker, P , Tutt, A , Ameer-Beg, SM & Ng, T 2014, 'The ErbB4 CYT2 variant protects EGFR from ligand-induced degradation to enhance cancer cell motility', Science Signaling, vol. 7, no. 339, ra78. https://doi.org/10.1126/scisignal.2005157

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

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.

KW - Breast Neoplasms

KW - Cell Line, Tumor

KW - Cell Movement

KW - Drug Resistance, Neoplasm

KW - Female

KW - GRB2 Adaptor Protein

KW - Humans

KW - Protein Structure, Tertiary

KW - Protein Transport

KW - Proteolysis

KW - Proto-Oncogene Proteins c-cbl

KW - Receptor, Epidermal Growth Factor

KW - Receptor, ErbB-4

U2 - 10.1126/scisignal.2005157

DO - 10.1126/scisignal.2005157

M3 - Article

C2 - 25140053

SN - 1945-0877

VL - 7

JO - Science Signaling

JF - Science Signaling

IS - 339

M1 - ra78

ER -

The ErbB4 CYT2 variant protects EGFR from ligand-induced degradation to enhance cancer cell motility

Abstract

Keywords

UN SDGs

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