Phe45 of NRG2β is critical for the affinity of NRG2β for ErbB4 and for potent stimulation of ErbB4 signaling by NRG2β*: Mini Review

The Neuregulins (NRGs) are members of the epidermal growth factor (EGF) family of growth factors. EGF family members regulate the signaling of ErbB family receptor tyrosine kinases, including the epidermal growth factor receptor (EGFR/ErbB1), ErbB2/HER2/Neu, ErbB3/HER3 and ErbB4/HER4. We have previously demonstrated that the EGF family hormone NRG2 beta is a potent ErbB4 agonist, whereas NRG2 alpha is a weak ErbB4 agonist. We have also previously demonstrated that Phe45 of NRG2 beta regulates the potency of NRG2 beta. Here, we address the hypotheses that Phe45 regulates the potency of NRG2 beta by regulating the affinity of NRG2 beta for ErbB4. We demonstrate that Phe45 of NRG2 beta indeed regulates the affinity of NRG2 beta for ErbB4. Furthermore, a hydrophobic or uncharged amino acid side chain at residue 45 contributes to NRG2 beta binding to ErbB4. These data indicate that Phe45 of NRG2 beta may regulate the affinity of NRG2 beta for ErbB4 by interacting with hydrophobic amino acids in ErbB4.