Neuregulin-4: a novel growth factor that acts through the ErbB-4 receptor tyrosine kinase.
The ErbB/HER family of receptor tyrosine kinases consists of four receptors that bind a large number of growth factor ligands sharing an epidermal growth factor- (EGF)-like motif. Whereas ErbB-1 binds seven different ligands whose prototype is EGF, the three families of neuregulins (NRGs) activate ErbB-3 and/or ErbB-4. Here we characterize a fourth neuregulin, NRG-4, that acts through ErbB-4. The predicted pro-NRG-4 is a transmembrane protein carrying a unique EGF-like motif and a short cytoplasmic domain. A synthetic peptide encompassing the full-length EGF-like domain can induce growth of interleukin-dependent cells ectopically expressing ErbB-4, but not cells expressing the other three ErbB proteins or their combinations. Consistent with specificity to ErbB-4, NRG-4 can displace an ErbB-4-bound NRG-1 and can activate signaling downstream of this receptor. Expression of NRG-4 mRNA was detected in the adult pancreas and weakly in muscle; other tissues displayed no detectable NRG-4 mRNA. The primary structure and the pattern of expression of NRG-4, together with the strict specificity of this growth factor to ErbB-4, suggest a physiological role distinct from that of the known ErbB ligands.
Harari
D
D
Department of Biological Regulation, The Weizmann Institute of Science, Rehovot, Israel.
Tzahar
E
E
Romano
J
J
Shelly
M
M
Pierce
J H
JH
Andrews
G C
GC
Yarden
Y
Y
D000595:Amino Acid Sequence; D001483:Base Sequence; D002455:Cell Division / Q000502:physiology; D066246:ErbB Receptors / Q000502:physiology*; D006023:Glycoproteins / Q000502:physiology*; D006801:Humans; D008024:Ligands; D008969:Molecular Sequence Data; D009414:Nerve Growth Factors / Q000502:physiology*; D020880:Neuregulins; D009928:Organ Specificity; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000096:biosynthesis; D066247:Receptor, ErbB-4
D006023:Glycoproteins; D008024:Ligands; D009414:Nerve Growth Factors; D020880:Neuregulins; D012333:RNA, Messenger; C587689:ERBB4 protein, human; D066246:ErbB Receptors; D066247:Receptor, ErbB-4