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Haenssen KK , Caldwell SA , Shahriari KS , Jackson SR , Whelan KA , Klein-Szanto AJ , Reginato MJ
ErbB2 requires integrin alpha 5 for anoikis resistance via Src regulation of receptor activity in human mammary epithelial cells
Journal of Cell Science. 2010 Apr;123(8) :1373-1382
AbstractErbB2, 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 alpha 5 via the MAP-kinase pathway in three-dimensional acini and found elevated integrin alpha 5 levels associated with ErbB2 status in human breast cancer. Integrin alpha 5 is required for ErbB2-mediated anoikis resistance and for optimal ErbB2 signaling to the Mek-Erk-Bim axis as depletion of integrin alpha 5 reverses anoikis resistance and Bim inhibition. Integrin alpha 5 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 alpha 5 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.
NotesHaenssen, Keneshia K. Caldwell, Sarah A. Shahriari, Kristina S. Jackson, S. RaElle Whelan, Kelly A. Klein-Szanto, Andres J. Reginato, Mauricio J. Company of biologists ltd Cambridge 582au