The crosstalk between ErbB1 and nucleolin

The ErbB receptor tyrosine kinases Tare major contributors to malig-nant 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 cyto-plasmic proteins, which initiate the cas-cade 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 phosphopro-tein that is also overexpressed in cancer cells. Overexpression of ErbB1 and nucle-olin may enhance receptor dimerization, phosphorylation and anchorage indepen-dent growth. Using mutational analyses, ErbB1 nuclear localization domain was identified as nucleolin interacting region. This region is important for nucleolin-associated receptor activation. In addi-tion, it was demonstrated that the 212 c-terminal portion of nucleolin is impor-tant for the interaction with ErbB1 and ErbB4. This region of nucleolin is suf-ficient 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.