Abstract
The neuregulins (NRGs) are members of the epidermal growth factor (EGF) family of peptide growth factors. These hormones are agonists for the ErbB family of receptor tyrosine kinases, a family that includes the epidermal growth factor receptor (EGFR/ErbB1), ErbB2/Neu/HER2, ErbB3/HER3, and ErbB4/HER4. We recently observed that the EGF family hormone NRG2β is a potent agonist for ErbB4. In contrast, NRG2α, a splicing isoform of the same gene that encodes NRG2β, is a poor ErbB4 agonist. We hypothesized that carboxyl-terminal residues of NRG2β are critical for stimulation of ErbB4 tyrosine phosphorylation and coupling to downstream signaling events. Here, we demonstrate that the substitution of a lysine residue for Phe45 in NRG2β results in reduced ligand potency. We also demonstrate that substitution of a phenylalanine for Lys45 in NRG2α results in increased ligand potency. Finally, analyses of the gain-of-function NRG2α Chg5 mutant demonstrate that Gln43, Met47, Asn49, and Phe50 regulate ligand efficacy. Thus, these data indicate that carboxyl-terminal residues of NRG2β are critical for activation of ErbB4 signaling. Moreover, these NRG2α and NRG2β mutants reveal new insights into models for ligand-induced ErbB family receptor tyrosine phosphorylation and coupling to downstream signaling events.
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Acknowledgements
SS Hobbs was supported by an NIH predoctoral training grant (T32GM008737). EM Cameron was supported by undergraduate research fellowships from the Carroll County (Indiana) Cancer Society and the American Foundation for Pharmaceutical Education. RP Hammer was supported by an NIH sabbatical leave fellowship (F33CA085049). We acknowledge additional support from the NIH (R21CA080770 and R21CA089274 to DJR), the US Army Medical Research and Materiel Command (DAMD17-00-1-0415, DAMD17-00-1-0416, and DAMD17-02-1-0130 to DJR), the Indiana Elks Foundation (to DJR) and American Cancer Society (IRG-58-006 to the Purdue Cancer Center).
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Hobbs, S., Cameron, E., Hammer, R. et al. Five carboxyl-terminal residues of neuregulin2 are critical for stimulation of signaling by the ErbB4 receptor tyrosine kinase. Oncogene 23, 883–893 (2004). https://doi.org/10.1038/sj.onc.1207250
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DOI: https://doi.org/10.1038/sj.onc.1207250