Cooperative but distinct early co-signaling events originate from ERBB2 and ERBB1 receptors upon trastuzumab treatment in breast cancer cells

Paola Bagnato, Alessia Castagnino, Katia Cortese, Maria Bono, Silvia Grasso, Grazia Bellese, Tiziana Daniele, Richard Lundmark, Paola Defilippi, Patrizio Castagnola, Carlo Tacchetti

Research output: Contribution to journalArticle

Abstract

ERBB2 receptor belongs to the ERBB tyrosine kinase receptor family. At variance to the other family members, ERBB2 is a constitutively active orphan receptor. Upon ligand binding and activation, ERBB receptors form homo- or hetero-dimers with the other family members, including ERBB2, promoting an intracellular signaling cascade. ERBB2 is the preferred dimerization partner and ERBB2 heterodimers signaling is stronger and longer acting compared to heterodimers between other ERBB members. The specific contribution of ERBB2 in heterodimer signaling is still undefined. Here we report the formation of circular dorsal ruffles (CDRs) upon treatment of the ERBB2-overexpressing breast cancer cell lines SK-BR-3 and ZR751 with Trastuzumab, a therapeutic humanized monoclonal antibody directed against ERBB2. We found that in SK-BR-3 cells Trastuzumab leads to surface redistribution of ERBB2 and ERBB1 in CDRs, and that the ERBB2-dependent ERK1/2 phosphorylation and ERBB1 expression are both required for CDR formation. In particular, in these cells CDR formation requires activation of both the protein regulator of actin polymerization N-WASP, mediated by ERK1/2, and of the actin depolymerizing protein cofilin, mediated by ERBB1. Furthermore, we suggest that this latter event may be inhibited by the negative cell motility regulator p140Cap, as we found that p140Cap overexpression led to cofilin deactivation and inhibition of CDR formation. In conclusion, here we show for the first time an ERBB2-specific signaling contribution to an ERBB2/ERBB1 heterodimer, in the activation of a complex biological process such as the formation of CDRs.

Original languageEnglish
Pages (from-to)60109-60122
Number of pages14
JournalOncotarget
Volume8
Issue number36
DOIs
Publication statusPublished - 2017

Fingerprint

Actin Depolymerizing Factors
Breast Neoplasms
Biological Phenomena
Antibodies, Monoclonal, Humanized
Receptor Protein-Tyrosine Kinases
Dimerization
Polymerization
Cell Movement
Actins
Phosphorylation
Ligands
Cell Line
Trastuzumab
Proteins
Therapeutics

Keywords

  • Breast cancer
  • Circular dorsal ruffles
  • ERBB1
  • ERBB2
  • Trastuzumab

ASJC Scopus subject areas

  • Oncology

Cite this

Cooperative but distinct early co-signaling events originate from ERBB2 and ERBB1 receptors upon trastuzumab treatment in breast cancer cells. / Bagnato, Paola; Castagnino, Alessia; Cortese, Katia; Bono, Maria; Grasso, Silvia; Bellese, Grazia; Daniele, Tiziana; Lundmark, Richard; Defilippi, Paola; Castagnola, Patrizio; Tacchetti, Carlo.

In: Oncotarget, Vol. 8, No. 36, 2017, p. 60109-60122.

Research output: Contribution to journalArticle

Bagnato, Paola ; Castagnino, Alessia ; Cortese, Katia ; Bono, Maria ; Grasso, Silvia ; Bellese, Grazia ; Daniele, Tiziana ; Lundmark, Richard ; Defilippi, Paola ; Castagnola, Patrizio ; Tacchetti, Carlo. / Cooperative but distinct early co-signaling events originate from ERBB2 and ERBB1 receptors upon trastuzumab treatment in breast cancer cells. In: Oncotarget. 2017 ; Vol. 8, No. 36. pp. 60109-60122.
@article{04b8053e6802478abe4255b30144ffaa,
title = "Cooperative but distinct early co-signaling events originate from ERBB2 and ERBB1 receptors upon trastuzumab treatment in breast cancer cells",
abstract = "ERBB2 receptor belongs to the ERBB tyrosine kinase receptor family. At variance to the other family members, ERBB2 is a constitutively active orphan receptor. Upon ligand binding and activation, ERBB receptors form homo- or hetero-dimers with the other family members, including ERBB2, promoting an intracellular signaling cascade. ERBB2 is the preferred dimerization partner and ERBB2 heterodimers signaling is stronger and longer acting compared to heterodimers between other ERBB members. The specific contribution of ERBB2 in heterodimer signaling is still undefined. Here we report the formation of circular dorsal ruffles (CDRs) upon treatment of the ERBB2-overexpressing breast cancer cell lines SK-BR-3 and ZR751 with Trastuzumab, a therapeutic humanized monoclonal antibody directed against ERBB2. We found that in SK-BR-3 cells Trastuzumab leads to surface redistribution of ERBB2 and ERBB1 in CDRs, and that the ERBB2-dependent ERK1/2 phosphorylation and ERBB1 expression are both required for CDR formation. In particular, in these cells CDR formation requires activation of both the protein regulator of actin polymerization N-WASP, mediated by ERK1/2, and of the actin depolymerizing protein cofilin, mediated by ERBB1. Furthermore, we suggest that this latter event may be inhibited by the negative cell motility regulator p140Cap, as we found that p140Cap overexpression led to cofilin deactivation and inhibition of CDR formation. In conclusion, here we show for the first time an ERBB2-specific signaling contribution to an ERBB2/ERBB1 heterodimer, in the activation of a complex biological process such as the formation of CDRs.",
keywords = "Breast cancer, Circular dorsal ruffles, ERBB1, ERBB2, Trastuzumab",
author = "Paola Bagnato and Alessia Castagnino and Katia Cortese and Maria Bono and Silvia Grasso and Grazia Bellese and Tiziana Daniele and Richard Lundmark and Paola Defilippi and Patrizio Castagnola and Carlo Tacchetti",
year = "2017",
doi = "10.18632/oncotarget.17686",
language = "English",
volume = "8",
pages = "60109--60122",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals LLC",
number = "36",

}

TY - JOUR

T1 - Cooperative but distinct early co-signaling events originate from ERBB2 and ERBB1 receptors upon trastuzumab treatment in breast cancer cells

AU - Bagnato, Paola

AU - Castagnino, Alessia

AU - Cortese, Katia

AU - Bono, Maria

AU - Grasso, Silvia

AU - Bellese, Grazia

AU - Daniele, Tiziana

AU - Lundmark, Richard

AU - Defilippi, Paola

AU - Castagnola, Patrizio

AU - Tacchetti, Carlo

PY - 2017

Y1 - 2017

N2 - ERBB2 receptor belongs to the ERBB tyrosine kinase receptor family. At variance to the other family members, ERBB2 is a constitutively active orphan receptor. Upon ligand binding and activation, ERBB receptors form homo- or hetero-dimers with the other family members, including ERBB2, promoting an intracellular signaling cascade. ERBB2 is the preferred dimerization partner and ERBB2 heterodimers signaling is stronger and longer acting compared to heterodimers between other ERBB members. The specific contribution of ERBB2 in heterodimer signaling is still undefined. Here we report the formation of circular dorsal ruffles (CDRs) upon treatment of the ERBB2-overexpressing breast cancer cell lines SK-BR-3 and ZR751 with Trastuzumab, a therapeutic humanized monoclonal antibody directed against ERBB2. We found that in SK-BR-3 cells Trastuzumab leads to surface redistribution of ERBB2 and ERBB1 in CDRs, and that the ERBB2-dependent ERK1/2 phosphorylation and ERBB1 expression are both required for CDR formation. In particular, in these cells CDR formation requires activation of both the protein regulator of actin polymerization N-WASP, mediated by ERK1/2, and of the actin depolymerizing protein cofilin, mediated by ERBB1. Furthermore, we suggest that this latter event may be inhibited by the negative cell motility regulator p140Cap, as we found that p140Cap overexpression led to cofilin deactivation and inhibition of CDR formation. In conclusion, here we show for the first time an ERBB2-specific signaling contribution to an ERBB2/ERBB1 heterodimer, in the activation of a complex biological process such as the formation of CDRs.

AB - ERBB2 receptor belongs to the ERBB tyrosine kinase receptor family. At variance to the other family members, ERBB2 is a constitutively active orphan receptor. Upon ligand binding and activation, ERBB receptors form homo- or hetero-dimers with the other family members, including ERBB2, promoting an intracellular signaling cascade. ERBB2 is the preferred dimerization partner and ERBB2 heterodimers signaling is stronger and longer acting compared to heterodimers between other ERBB members. The specific contribution of ERBB2 in heterodimer signaling is still undefined. Here we report the formation of circular dorsal ruffles (CDRs) upon treatment of the ERBB2-overexpressing breast cancer cell lines SK-BR-3 and ZR751 with Trastuzumab, a therapeutic humanized monoclonal antibody directed against ERBB2. We found that in SK-BR-3 cells Trastuzumab leads to surface redistribution of ERBB2 and ERBB1 in CDRs, and that the ERBB2-dependent ERK1/2 phosphorylation and ERBB1 expression are both required for CDR formation. In particular, in these cells CDR formation requires activation of both the protein regulator of actin polymerization N-WASP, mediated by ERK1/2, and of the actin depolymerizing protein cofilin, mediated by ERBB1. Furthermore, we suggest that this latter event may be inhibited by the negative cell motility regulator p140Cap, as we found that p140Cap overexpression led to cofilin deactivation and inhibition of CDR formation. In conclusion, here we show for the first time an ERBB2-specific signaling contribution to an ERBB2/ERBB1 heterodimer, in the activation of a complex biological process such as the formation of CDRs.

KW - Breast cancer

KW - Circular dorsal ruffles

KW - ERBB1

KW - ERBB2

KW - Trastuzumab

UR - http://www.scopus.com/inward/record.url?scp=85030481147&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85030481147&partnerID=8YFLogxK

U2 - 10.18632/oncotarget.17686

DO - 10.18632/oncotarget.17686

M3 - Article

AN - SCOPUS:85030481147

VL - 8

SP - 60109

EP - 60122

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 36

ER -