Journal article
ErbB2 requires integrin α5 for anoikis resistance via Src regulation of receptor activity in human mammary epithelial cells
Journal of cell science, v 123(8), pp 1373-1382
15 Apr 2010
PMID: 20332114
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
ErbB2, a receptor tyrosine kinase highly expressed in many tumors, is known to inhibit apoptotic signals. Overexpression of ErbB2 causes anoikis resistance that contributes to luminal filling in three-dimensional mammary epithelial acinar structures in vitro. Given that integrins and growth factor receptors are highly interdependent for function, we examined the role of integrin subunits in ErbB2-mediated survival signaling. Here, we show that MCF-10A cells overexpressing ErbB2 upregulate integrin α5 via the MAP-kinase pathway in three-dimensional acini and found elevated integrin α5 levels associated with ErbB2 status in human breast cancer. Integrin α5 is required for ErbB2-mediated anoikis resistance and for optimal ErbB2 signaling to the Mek-Erk-Bim axis as depletion of integrin α5 reverses anoikis resistance and Bim inhibition. Integrin α5 is required for full activation of ErbB2 tyrosine phosphorylation on Y877 and ErbB2 phosphorylation is associated with increased activity of Src in the absence of adhesion. Indeed, we show that blocking elevated Src activity during cell detachment reverses ErbB2-mediated survival and Bim repression. Thus, integrin α5 serves as a key mediator of Src and ErbB2-survival signaling in low adhesion states, which are necessary to block the pro-anoikis mediator Bim, and we suggest that this pathway represents a potential novel therapeutic target in ErbB2-positive tumors.
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Details
- Title
- ErbB2 requires integrin α5 for anoikis resistance via Src regulation of receptor activity in human mammary epithelial cells
- Creators
- Keneshia K Haenssen - Department of Biochemistry and Molecular Biology, 245 N. 15Sarah A Caldwell - Department of Biochemistry and Molecular Biology, 245 N. 15Kristina S Shahriari - Department of Biochemistry and Molecular Biology, 245 N. 15S. RaElle Jackson - Department of Biochemistry and Molecular Biology, 245 N. 15Kelly A Whelan - Department of Biochemistry and Molecular Biology, 245 N. 15Andres J Klein-Szanto - Department of Pathology, Fox Chase Cancer CenterMauricio J Reginato - Department of Biochemistry and Molecular Biology, 245 N. 15
- Publication Details
- Journal of cell science, v 123(8), pp 1373-1382
- Publisher
- Company of Biologists
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology
- Web of Science ID
- WOS:000276568200020
- Scopus ID
- 2-s2.0-77951169413
- Other Identifier
- 991014878443104721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Cell Biology