Mol Cancer Ther 2006, 5 (5) : 1239–1247.CrossRefPubMed

Competing interests The authors declare that they have no competing interests. Authors’ contributions LX and LW carried out cell treatments and radiosensitivity assay; BS, XW and LL contributed to MTT cell viability assay and flow check details cytometry analysis. LX, XS and JY supervised experimental work and ARS-1620 purchase wrote the manuscript. All authors read and approved the final manuscript.”
“Background Integrins are an important class of cell surface receptors that recognize extracellular matrix proteins and allow the cell’s microenvironment to help regulate intracellular signaling events[1, 2]. Binding to multivalent ligands results in integrin crosslinking, which activates a signaling process that induces integrin clustering within the plasma membrane[3, 4]. Clustering of integrins in vitro can also be investigated with crosslinking antibodies, which provide greater specificity than most integrin ligands[5]. In the process of integrin clustering, integrins that are diffusely distributed throughout the membrane dissociate from their cytoskeletal contacts and aggregate in particular regions of the membrane, where they form large complexes with new attachments to the cytoskeleton[6,

7]. In addition to activating the individual integrin heterodimers, the clustering of integrins leads to recruitment of other signaling molecules to the plasma membrane [1–4]. Activated integrins are known to regulate growth factor receptor signaling in normal and malignant cells[8, 9]. Integrin-growth factor receptor crosstalk is important for many growth factor receptor-mediated selleck screening library functions, including cell proliferation, survival, motility and invasion[8, 9]. The α6β4 integrin, a receptor for most laminins that is normally expressed in the myoepithelial cell layer of benign breast epithelium[10], is upregulated in the aggressive basal subtype of invasive breast cancer[11]. EGFR is also overexpressed in this subgroup of breast cancers[11], and in-vitro data suggest that crosstalk between α6β4 integrin

Non-specific serine/threonine protein kinase and EGFR may be important in the progression of this basal subtype of breast cancers [12–14]. EGFR converts from an inactive monomeric form to an active homodimer upon stimulation by its ligand[15, 16], and cell surface clusters of activated EGFR homodimers are known to occur [17–19]. We showed previously that α6β4 integrin crosslinking induces PI3K-dependent cell surface clustering of α6β4 integrin in breast carcinoma cells[20]. Because integrin clusters are known to recruit other molecules to membrane complexes, we hypothesized that α6β4 clustering might lead to the redistribution and clustering of EGFR on the tumor cell surface. Moreover, because cell surface clustering of a variety of receptors, including EGFR, has been shown to augment receptor function[5, 17–19], we hypothesized that α6β4 integrin-induced EGFR clustering might augment particular tumor cell responses to EGF.