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A putative molecular-activation switch in the transmembrane domain of erbB2

Sarel J Fleishman1, Joseph Schlessinger, Nir Ben-Tal

  • 1Department of Biochemistry, The George S. Wise Faculty of Life Sciences, Tel-Aviv University, Ramat-Aviv 69987, Israel Middle East.

Proceedings of the National Academy of Sciences of the United States of America
|December 4, 2002
PubMed

Insights

Overexpression of the receptor tyrosine kinase (RTK) erbB2 (HER2) drives cancer. This study reveals a molecular mechanism for erbB2 activation, identifying distinct active and inactive states crucial for its oncogenic function.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Receptor tyrosine kinases (RTKs), like erbB2 (HER2), are crucial in cell signaling.
  • Overexpression of erbB2 is linked to various human cancers, including breast and ovarian carcinomas.
  • Ligand-induced dimerization and subsequent protein tyrosine kinase (PTK) activation are key to RTK function.

Purpose of the Study:

  • To elucidate the molecular mechanism behind erbB2 receptor activation.
  • To investigate the role of transmembrane (TM) domain conformations in erbB2 activity.
  • To explain the oncogenic properties and differential effects of mutations/polymorphisms on erbB2.

Main Methods:

  • Computational exploration of the conformational space of erbB2 transmembrane segments.
  • Analysis of stable conformations representing active and inactive states of the erbB2 homodimer.
  • Modeling the transition between these conformations.

Main Results:

  • Identified two stable conformations of the erbB2 TM domain, proposed as active and inactive states.
  • Demonstrated that erbB2 can transition between these states without significant energy barriers.
  • Provided a model explaining erbB2 overexpression effects on kinase activity and cell transformation.

Conclusions:

  • The proposed rotation-coupled activation mechanism explains erbB2's biochemical and oncogenic properties.
  • The model accounts for the opposing effects of activating mutations and protective polymorphisms on erbB2 activity.
  • This provides insights into cancer development and potential therapeutic strategies targeting erbB2.

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