Biased activation of the receptor tyrosine kinase HER2

TY - UNPB

T1 - Biased activation of the receptor tyrosine kinase HER2

AU - Catapano, Claudia

AU - Rahm, Johanna V

AU - Omer, Marjan

AU - Teodori, Laura

AU - Kjems, Jørgen

AU - Dietz, Marina S

AU - Heilemann, Mike

PY - 2022/12/1

Y1 - 2022/12/1

N2 - 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$1 showed weaker activation of HER2, a preference for EREG and a delayed response to NRG$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. Highlights ![Figure][1]textless/imgtextgreater Competing Interest Statement The authors have declared no competing interest. [1]: pending:yes

AB - 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$1 showed weaker activation of HER2, a preference for EREG and a delayed response to NRG$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. Highlights ![Figure][1]textless/imgtextgreater Competing Interest Statement The authors have declared no competing interest. [1]: pending:yes

KW - HER2

KW - biased signaling

KW - live-cell imaging

KW - receptor tyrosine kinase

KW - single-particle tracking

U2 - 10.1101/2022.12.04.519064

DO - 10.1101/2022.12.04.519064

M3 - Preprint

BT - Biased activation of the receptor tyrosine kinase HER2

PB - bioRxiv

ER -