Hobbs Stuart S, Coffing Stephanie L, Le Ann T D, Cameron Elizabeth M, Williams Eric E, Andrew Michelle, Blommel Erika N, Hammer Robert P, Chang Han, Riese David J
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University School of Pharmacy, West Lafayette, Indiana, IN 7907-1333, USA.
Oncogene. 2002 Dec 5;21(55):8442-52. doi: 10.1038/sj.onc.1205960.
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.
在过去十年中，已经鉴定出几种肽生长因子的表皮生长因子家族的新成员。其中最突出的是神经调节蛋白或神经调节素。迄今为止，已鉴定出四种不同的神经调节蛋白基因（神经调节蛋白1 - 4），并且已为其中至少两个基因（神经调节蛋白1和神经调节蛋白2）鉴定出几种不同的剪接异构体。虽然神经调节蛋白1异构体已被广泛研究，但对神经调节蛋白3、神经调节蛋白4或神经调节蛋白2异构体的了解相对较少。实际上，尚未对这些分子的活性进行系统比较。在这里，我们证明神经调节蛋白2α和神经调节蛋白2β刺激ErbB3酪氨酸磷酸化并与生物学反应偶联。相比之下，神经调节蛋白3和神经调节蛋白4未能激活ErbB3信号传导。此外，神经调节蛋白2β而非神经调节蛋白2α刺激ErbB4酪氨酸磷酸化并与生物学反应偶联。最后，神经调节蛋白3和神经调节蛋白4均刺激适度量的ErbB4酪氨酸磷酸化。然而，虽然神经调节蛋白3刺激适度量的ErbB4与生物学反应偶联，但神经调节蛋白4未能刺激ErbB4与生物学反应偶联。这表明神经调节蛋白异构体在激活ErbB家族受体方面存在质和量的差异。
