Neuregulin isoforms exhibit distinct patterns of ErbB family receptor activation.
During the last decade, several novel members of the Epidermal Growth Factor family of peptide growth factors have been identified. Most prominent among these are the Neuregulins or Heregulins. To date, four different Neuregulin genes have been identified (Neuregulin1-4) and several different splicing isoforms have been identified for at least two of these genes (Neuregulin1 and Neuregulin2). While Neuregulin1 isoforms have been extensively studied, comparatively little is known about Neuregulin3, Neuregulin4, or the Neuregulin2 isoforms. Indeed, there has been no systematic comparison of the activities of these molecules. Here we demonstrate that Neuregulin2alpha and Neuregulin2beta stimulate ErbB3 tyrosine phosphorylation and coupling to biological responses. In contrast, Neuregulin3 and Neuregulin4 fail to activate ErbB3 signaling. Furthermore, Neuregulin2beta, but not Neuregulin2alpha, stimulates ErbB4 tyrosine phosphorylation and coupling to biological responses. Finally, both Neuregulin3 and Neuregulin4 stimulate modest amounts of ErbB4 tyrosine phosphorylation. However, whereas Neuregulin3 stimulates a modest amount of ErbB4 coupling to biological responses, Neuregulin4 fails to stimulate ErbB4 coupling to biological responses. This suggests that there are qualitative as well as quantitative differences in ErbB family receptor activation by Neuregulin isoforms.
Hobbs
Stuart S
SS
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University School of Pharmacy, West Lafayette, Indiana, IN 7907-1333, USA.
Coffing
Stephanie L
SL
Le
Ann T D
AT
Cameron
Elizabeth M
EM
Williams
Eric E
EE
Andrew
Michelle
M
Blommel
Erika N
EN
Hammer
Robert P
RP
Chang
Han
H
Riese
David J
DJ
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D003001:Cloning, Molecular; D017931:DNA Primers; D004331:Drosophila melanogaster; D066246:ErbB Receptors / Q000235:genetics*; D005786:Gene Expression Regulation / Q000502:physiology; D018815:Genes, erbB; D020880:Neuregulins / Q000235:genetics / Q000502:physiology*; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection
D017931:DNA Primers; D020880:Neuregulins; D020033:Protein Isoforms; D011994:Recombinant Proteins; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases