Biased activation of the receptor tyrosine kinase HER2

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 TGFa, yet with a distinguishable temporal fingerprint. The HER4-targeting ligands EREG and NRG beta 1 showed weaker activation of HER2, a preference for EREG, and a delayed response to NRG beta 1. 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. [GRAPHICS] .

Automated summary

HER2 belongs to the ErbB sub-family of receptor tyrosine kinases and is activated through heterodimerization with other ErbB receptors. This study found that HER2 is strongly activated by EGFR-targeting ligands EGF and TGFa, with a distinguishable temporal fingerprint. HER4-targeting ligands EREG and NRG beta 1 showed weaker activation of HER2, with a preference for EREG and a delayed response to NRG beta 1.