Abstract
Signaling via the ErbB-family of receptors plays an important role in mammalian development and oncogenesis. Here we show that the ErbB-3 receptor, but not other members of this receptor family, binds to immobilized heparin and can be dissociated only at a high ionic strength comparable to that required for fibroblast growth factor receptors. Competition-binding analysis suggests that this interaction is specific and requires highly sulfated species of heparan sulfate. Primary sequence analysis of ErbB-3 identified a basic amino acid cluster (466)KHNRPRR(472) localized to the proximal, cysteine-rich extracellular ligand binding domain of the receptor, with charge density and distribution compatible with, but different to, known linear heparin binding motifs. Site-directed mutagenesis, replacing this sequence with the corresponding residues from ErbB-1, resulted in complete loss of heparin binding activity of the chimeric receptor. Finally, antibodies directed to the putative heparin binding peptide, efficiently bind the native receptor suggesting a novel target for blocking heparin mediated ErbB-3 interactions.
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