Inter-conversion of neuregulin2 full and partial agonists for ErbB4.
The EGF family hormone NRG2beta potently stimulates ErbB4 tyrosine phosphorylation and coupling to IL3 independence. In contrast, the NRG2alpha splicing isoform has lower affinity for ErbB4, does not potently stimulate ErbB4 phosphorylation, and fails to stimulate ErbB4 coupling. Here we investigate these differences. The NRG2beta Q43L mutant potently stimulates ErbB4 phosphorylation but not ErbB4 coupling to IL3 independence. This failure to stimulate ErbB4 coupling is not due to differential ligand purity, glycosylation, or stability. The NRG2alpha K45F mutant potently stimulates ErbB4 phosphorylation but not ErbB4 coupling to IL3 independence. Thus, this failure to stimulate ErbB4 coupling is not due to inadequate affinity for ErbB4. In contrast, the NRG2alpha L43Q/K45F mutant stimulates ErbB4 coupling, even though it does not have greater affinity for ErbB4 than does NRG2alpha/K45F. Collectively, these data indicate that Gln43 of NRG2beta is both necessary and sufficient for NRG2 stimulation of ErbB4 coupling to IL3 independence.
Wilson
Kristy J
KJ
Purdue University School of Pharmacy, Purdue Cancer Research Center, HANS 114, 201 S. University Street, West Lafayette, IN 47907-2064, USA.
Mill
Christopher P
CP
Cameron
Elizabeth M
EM
Hobbs
Stuart S
SS
Hammer
Robert P
RP
Riese
David J
DJ
D000595:Amino Acid Sequence; D002460:Cell Line; D066246:ErbB Receptors / Q000819:agonists / Q000378:metabolism*; D005998:Glycine / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007377:Interleukin-3 / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D010766:Phosphorylation; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D019154:Protein Splicing; D066247:Receptor, ErbB-4; D011994:Recombinant Proteins / Q000494:pharmacology; D014443:Tyrosine / Q000378:metabolism
C508596:IL3 protein, human; D007377:Interleukin-3; C106766:NRG2 protein, human; D009414:Nerve Growth Factors; D020033:Protein Isoforms; D011994:Recombinant Proteins; D014443:Tyrosine; C587689:ERBB4 protein, human; D066246:ErbB Receptors; D066247:Receptor, ErbB-4; D005998:Glycine