Abstract
BackgroundThe ErbB receptor tyrosine kinases are major contributors to malignant transformation. These receptors are frequently overexpressed in a variety of human carcinomas. The role of the ErbB receptors and their ligands in carcinomas and the mechanism by which their overexpression leads to cancer development is still unclear. Ligand binding to specific ErbB receptor is followed by receptor dimerization, phosphorylation and recruitment of SH2 containing cytoplasmic proteins, which initiate the cascade of signaling events. Nevertheless, increasing data suggest that there are non-phosphorylated receptor–substrate interactions that may affect ErbB-mediated responses.Methodology/Principal FindingsIn the present study, using GST-ErbB4 fusion protein pull down assay and mass spectroscopic analysis, we have found the ErbB receptors interact with nucleolin via their cytoplasmic tail. Nucleolin is a ubiquitous, nonhistone, nucleolar, multifunctional phosphoprotein that is also overexpressed in cancer cells. Our results demonstrate that overexpression of ErbB1 and nucleolin may lead to receptor dimerization, phosphorylation and to anchorage independent growth.Conclusions/SignificanceThe oncogenic potential of ErbB depends on receptor levels and activation. Our results suggest that nucleolin may affect ErbB dimerization and activation leading to enhanced cell growth.
Highlights
The ErbB subfamily of receptor tyrosine kinase contains four members: the epidermal growth factor (EGF) receptor [1], Neu/HER-2/ErbB-2 [2,3,4], HER-3/ErbB-3 [5,6] and HER-4/ErbB-4 [7]
ErbB receptors interact with nucleolin To identify new ErbB4 interacting proteins we used a pull down assay
Nucleolin enhances ErbB1 receptor dimerization To address the possibility that nucleolin induces the competence of ErbB receptor dimerization and trans-auto-phosphorylation, we examined the effect of nucleolin on receptor dimerization
Summary
The ErbB subfamily of receptor tyrosine kinase contains four members: the epidermal growth factor (EGF) receptor ( called ErbB-1) [1], Neu/HER-2/ErbB-2 [2,3,4], HER-3/ErbB-3 [5,6] and HER-4/ErbB-4 [7]. Ligand binding to ErbB receptors induces the formation of receptor homo- and heterodimers and activation of the intrinsic kinase domain, resulting in phosphorylation on specific tyrosine residues within the cytoplasmic tail. These phosphorylated residues serve as docking sites for a range of proteins, the recruitment of which leads to the activation of intracellular signaling pathways [10]. Increasing data suggest that there are nonphosphorylated receptor–substrate interactions that may affect ErbB-mediated responses
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