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Structure-function analysis of nucleolin and ErbB receptors interactions

Keren Farin1, Ayelet Di Segni, Adam Mor

  • 1Department of Neurobiology, Tel-Aviv University, Ramat-Aviv, Israel.

Plos One
|July 7, 2009
PubMed
Abstract

Insights

The interaction between ErbB receptors and nucleolin is crucial for cancer growth. Specific regions of ErbB1 and nucleolin mediate this interaction, driving malignant cell proliferation and receptor activation.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Oncology

Background:

  • ErbB receptor tyrosine kinases and nucleolin are key factors in malignant transformation.
  • Cell-surface ErbB receptors interact with nucleolin through their cytoplasmic tail.
  • Overexpression of ErbB1 and nucleolin promotes receptor phosphorylation, dimerization, and anchorage-independent growth.

Purpose of the Study:

  • To investigate the specific regions of nucleolin and ErbB involved in their interaction.
  • To elucidate the structure-function relationship governing the ErbB1-nucleolin interaction.
  • To understand how this interaction contributes to malignant cell behavior.

Main Methods:

  • Utilized mutational analyses to probe the ErbB1-nucleolin interaction.
  • Identified critical domains within ErbB1 and nucleolin responsible for binding.
  • Assessed the functional consequences of these interactions on receptor activity and cell growth.

Main Results:

  • The ErbB1 nuclear localization domain (NLS) was identified as the nucleolin-interacting region, essential for nucleolin-associated receptor activation.
  • While the tyrosine kinase domain is vital for receptor activation, it does not participate in nucleolin/ErbB binding.
  • The C-terminal 212 amino acids of nucleolin are imperative for interaction with ErbB1 and ErbB4 and can independently induce ErbB1 dimerization, phosphorylation, and anchorage-independent growth.

Conclusions:

  • Nucleolin modulates ErbB dimerization and activation, thereby enhancing cell growth and contributing to the oncogenic potential of ErbB.
  • The interaction is mediated by the nucleolin C-terminal region and the ErbB1 NLS-domain.
  • Targeting this ErbB1-nucleolin interaction may offer new therapeutic strategies for cancers driven by these proteins.

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