Shc is required for ErbB2-induced inhibition of apoptosis but is dispensable for cell proliferation and disruption of cell polarity

Lucs, A. V., Muller, W. J., Muthuswamy, S. K. (January 2010) Shc is required for ErbB2-induced inhibition of apoptosis but is dispensable for cell proliferation and disruption of cell polarity. Oncogene, 29 (2). pp. 174-187. ISSN 0950-9232

[img]
Preview
PDF (Shc is required for ErbB2-induced inhibition of apoptosis but is dispensable for cell proliferation and disruption of cell polarity)
Shc_is_required_for_ErbB2-induced_inhibition_of_apoptosis_but_is_dispensable_for_cell_proliferation_and_disruption_of_cell_polarity.pdf

Download (1442Kb)
URL: http://www.ncbi.nlm.nih.gov/pubmed/19826412
DOI: 10.1038/onc.2009.312

Abstract

Amplification and overexpression of ErbB2 strongly correlates with aggressive breast cancers. A deeper understanding of pathways downstream of ErbB2 signaling that are required for the transformation of human mammary epithelial cells will identify novel strategies for therapeutic intervention in breast cancer. Using an inducible activation of ErbB2 autophosphorylation qsite mutants and the MCF-10A three-dimensional (3D) culture system, we investigated pathways used by ErbB2 to transform the epithelia. We report that ErbB2 induces cell proliferation and loss of 3D organization by redundant mechanisms, whereas it disrupts apical basal polarity and inhibits apoptosis using Tyr 1201 and Tyr 1226/7, respectively. Signals downstream of Tyr 1226/7 were also sufficient to confer paclitaxel resistance. The Tyr 1226/7 binds Shc, and the knockdown of Shc blocks the ability of ErbB2 to inhibit apoptosis and mediate paclitaxel resistance. Tyr 1226/7 is known to activate the Ras/Erk pathway; however, paclitaxel resistance did not correlate with the activation of Erk or Akt, suggesting the presence of a novel mechanism. Thus, our results show that targeting pathways used by ErbB2 to inhibit cell death is a better option than targeting cell proliferation pathways. Furthermore, we identify a novel function for Shc as a regulator of apoptosis and drug resistance in human mammary epithelial cells transformed by ErbB2. Oncogene (2010) 29, 174-187; doi:10.1038/onc.2009.312; published online 12 October 2009

Item Type: Paper
Uncontrolled Keywords: ErbB2 apoptosis 3D culture taxol Shc MCF-10A HUMAN-BREAST-CANCER MAMMARY TUMORIGENESIS ADAPTER PROTEINS ERBB2 TRANSFORMATION ACTIVATION RESISTANCE RECEPTORS ONCOGENE KINASE
Subjects: bioinformatics > genomics and proteomics > analysis and processing > NETBAG
organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > apoptosis
diseases & disorders > cancer > cancer types > breast cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > kinase > tyrosine kinase
CSHL Authors:
Communities: CSHL labs > Muthuswamy lab
CSHL Cancer Center Shared Resources > DNA Sequencing Service
CSHL Cancer Center Shared Resources > Flow Cytometry Service
CSHL Cancer Center Shared Resources > Microscopy Service
CSHL Cancer Center Shared Resources > Instrumentation Service
Depositing User: CSHL Librarian
Date: 14 January 2010
Date Deposited: 03 Oct 2011 20:14
Last Modified: 30 Dec 2014 16:32
PMCID: PMC2948752
Related URLs:
URI: http://repository.cshl.edu/id/eprint/15467

Actions (login required)

Administrator's edit/view item Administrator's edit/view item
CSHL HomeAbout CSHLResearchEducationNews & FeaturesCampus & Public EventsCareersGiving