Phe45 of NRG2β is critical for the affinity of NRG2β for ErbB4 and for potent stimulation of ErbB4 signaling by NRG2β

Abstract

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 NRG2β is a potent ErbB4 agonist, whereas NRG2α is a weak ErbB4 agonist. We have also previously demonstrated that Phe45 of NRG2β regulates the potency of NRG2β. Here, we address the hypotheses that Phe45 regulates the potency of NRG2β by regulating the affinity of NRG2β for ErbB4. We demonstrate that Phe45 of NRG2β indeed regulates the affinity of NRG2β for ErbB4. Furthermore, a hydrophobic or uncharged amino acid side chain at residue 45 contributes to NRG2β binding to ErbB4. These data indicate that Phe45 of NRG2β may regulate the affinity of NRG2β for ErbB4 by interacting with hydrophobic amino acids in ErbB4.

• ErbB4
• signal transduction
• neuregulins
• epidermal growth factor