Abstract
BackgroundThe ErbB receptor tyrosine kinases and nucleolin are major contributors to malignant transformation. Recently we have found that cell-surface ErbB receptors interact with nucleolin via their cytoplasmic tail. Overexpression of ErbB1 and nucleolin leads to receptor phosphorylation, dimerization and anchorage independent growth.Methodology/Principal FindingsIn the present study we explored the regions of nucleolin and ErbB responsible for their interaction. Using mutational analyses, we addressed the structure–function relationship of the interaction between ErbB1 and nucleolin. We identified the ErbB1 nuclear localization domain as nucleolin interacting region. This region is important for nucleolin-associated receptor activation. Notably, though the tyrosine kinase domain is important for nucleolin-associated receptor activation, it is not involved in nucleolin/ErbB interactions. In addition, we demonstrated that the 212 c-terminal portion of nucleolin is imperative for the interaction with ErbB1 and ErbB4. This region of nucleolin is sufficient to induce ErbB1 dimerization, phosphorylation and growth in soft agar.Conclusions/SignificanceThe oncogenic potential of ErbB depends on receptor levels and activation. Nucleolin affects ErbB dimerization and activation leading to enhanced cell growth. The C-terminal region of nucleolin and the ErbB1 NLS-domain mediate this interaction. Moreover, when the C-terminal 212 amino acids region of nucleolin is expressed with ErbB1, it can enhance anchorage independent cell growth. Taken together these results offer new insight into the role of ErbB1 and nucleolin interaction in malignant cells.
Highlights
The ErbB subfamily of receptor tyrosine kinases (RTK) consists of four receptors: epidermal growth factor receptor (EGFR,HER1,ErbB1), HER2 (ErbB2,neu), HER3 (ErbB3) and HER4 (ErbB4) [1,2,3,4,5,6,7]
In the present study we demonstrate that ErbB1 juxtamembrane region, which is important for ErbB1 kinase activation [32], is important for nucleolin-ErbB1 interaction and nucleolin-induced ErbB1 dimerization and activation
Only two mutants failed to be precipitated by nucleolin; DCyt 1 and DNLS. These results suggest that the region in ErbB1, important for nucleolin binding, may be the ErbB1 nuclear localization sequence (NLS) (RRRHIVRKRTLRR)
Summary
The ErbB subfamily of receptor tyrosine kinases (RTK) consists of four receptors: epidermal growth factor receptor (EGFR,HER1,ErbB1), HER2 (ErbB2,neu), HER3 (ErbB3) and HER4 (ErbB4) [1,2,3,4,5,6,7]. These receptors are mediators of growth signals and determine cell fate. They are cell surface allosteric enzymes consisting of a single transmembrane domain that separates the intracellular kinase domain from the extracellular ligand-binding domain. Overexpression of ErbB1 and nucleolin leads to receptor phosphorylation, dimerization and anchorage independent growth
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