High- and low-affinity epidermal growth factor receptor-ligand interactions activate distinct signaling pathways.
Signaling mediated by the Epidermal Growth Factor Receptor (EGFR) is crucial in normal development, and aberrant EGFR signaling has been implicated in a wide variety of cancers. Here we find that the high- and low-affinity interactions between EGFR and its ligands activate different signaling pathways. While high-affinity ligand binding is sufficient for activation of most canonical signaling pathways, low-affinity binding is required for the activation of the Signal transducers and activators of transcription (Stats) and Phospholipase C-gamma 1 (PLCγ1). As the Stat proteins are involved in many cellular responses including proliferation, migration and apoptosis, these results assign a function to low-affinity interactions that has been omitted from computational models of EGFR signaling. The existence of receptors with distinct signaling properties provides a way for EGFR to respond to different concentrations of the same ligand in qualitatively different ways.
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, United States of America.
Jordan A
JA
Krall
Elsa M
EM
Beyer
Gavin
G
MacBeath
D002460:Cell Line; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D051966:Phospholipase C gamma / Q000378:metabolism; D011485:Protein Binding; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction
D008024:Ligands; D050791:STAT Transcription Factors; D066246:ErbB Receptors; D051966:Phospholipase C gamma
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