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 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 TGF, 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. HighlightsO_LIHER2 exhibits heterogeneous motion in the plasma membrane C_LIO_LIThe fraction of immobile HER2 correlates with phosphorylation levels C_LIO_LIDiffusion properties serve as proxies for HER2 activation C_LIO_LIHER2 exhibits ligand-specific activation strength and temporal profiles C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/519064v2_ufig1.gif" ALT="Figure 1"> View larger version (55K): org.highwire.dtl.DTLVardef@172415eorg.highwire.dtl.DTLVardef@21bf95org.highwire.dtl.DTLVardef@1a907aforg.highwire.dtl.DTLVardef@37a85a_HPS_FORMAT_FIGEXP M_FIG C_FIG