Harari D, Tzahar E, Romano J, Shelly M, Pierce J H, Andrews G C, Yarden Y
Department of Biological Regulation, The Weizmann Institute of Science, Rehovot, Israel.
Oncogene. 1999 Apr 29;18(17):2681-9. doi: 10.1038/sj.onc.1202631.
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.
受体酪氨酸激酶的ErbB/HER家族由四种受体组成，这些受体可结合大量具有表皮生长因子（EGF）样基序的生长因子配体。ErbB-1可结合七种不同的配体，其原型为EGF，而神经调节蛋白（NRG）的三个家族可激活ErbB-3和/或ErbB-4。在此，我们鉴定了一种通过ErbB-4起作用的第四种神经调节蛋白NRG-4。预测的前体NRG-4是一种跨膜蛋白，带有独特的EGF样基序和一个短的胞质结构域。包含全长EGF样结构域的合成肽可诱导异位表达ErbB-4的白细胞介素依赖性细胞生长，但不能诱导表达其他三种ErbB蛋白或其组合的细胞生长。与对ErbB-4的特异性一致，NRG-4可取代与ErbB-4结合的NRG-1，并可激活该受体下游的信号传导。在成年胰腺中检测到NRG-4 mRNA的表达，在肌肉中表达较弱；其他组织未检测到NRG-4 mRNA。NRG-4的一级结构和表达模式，以及这种生长因子对ErbB-4的严格特异性，提示其生理作用不同于已知的ErbB配体。
