Biased activation of the receptor tyrosine kinase HER2

Claudia Catapano, Johanna V. Rahm, Marjan Omer, Laura Teodori, Jørgen Kjems, Marina S. Dietz, Mike Heilemann*

*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Abstract

HER2 belongs to the ErbB sub-family of receptor tyrosine kinases and regulates cellular proliferation and growth. Different from other ErbB receptors, HER2 has no known ligand. Activation occurs through heterodimerization with other ErbB receptors and their cognate ligands. This suggests several possible activation paths of HER2 with ligand-specific, differential response, which has so far remained unexplored. Using single-molecule tracking and the diffusion profile of HER2 as a proxy for activity, we measured the activation strength and temporal profile in live cells. We found that HER2 is strongly activated by EGFR-targeting ligands EGF and TGFα, yet with a distinguishable temporal fingerprint. The HER4-targeting ligands EREG and NRGβ1 showed weaker activation of HER2, a preference for EREG, and a delayed response to NRGβ1. Our results indicate a selective ligand response of HER2 that may serve as a regulatory element. Our experimental approach is easily transferable to other membrane receptors targeted by multiple ligands. Graphical abstract: [Figure not available: see fulltext.]

Original languageEnglish
Article number158
JournalCellular and Molecular Life Sciences
Volume80
Issue6
ISSN1420-682X
DOIs
Publication statusPublished - Jun 2023

Keywords

  • Biased signaling
  • HER2
  • Live-cell imaging
  • Receptor tyrosine kinase
  • Single-particle tracking

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