The crosstalk between ErbB1 and nucleolin

Abstract

The ErbB receptor tyrosine kinases are major contributors to malignant transformation. These receptors are frequently overexpressed in a variety of human carcinomas. 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 receptor–substrate interactions that may affect ErbB-mediated responses that do not depend on receptor phosphorylation. Recently we demonstrated that the ErbB receptors interact with nucleolin protein via their cytoplasmic tail.  Nucleolin is a nucleolar, multifunctional phosphoprotein that is also overexpressed in cancer cells.  Overexpression of ErbB1 and nucleolin may enhance receptor dimerization, phosphorylation and anchorage independent growth. Using mutational analyses, ErbB1 nuclear localization domain was identified as nucleolin interacting region. This region is important for nucleolin-associated receptor activation.  In addition, it was demonstrated that the 212 c-terminal portion of nucleolin is important for the interaction with ErbB1 and ErbB4. This region of nucleolin is sufficient to enhance ErbB1 dimerization, phosphorylation and growth in soft agar. Taken together these findings imply that nucleolin may affect ErbB-mediated responses in malignant cells.

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