Epidermal growth factor-related peptides activate distinct subsets of ErbB receptors and differ in their biological activities
Epidermal growth factor-related peptides activate distinct subsets of ErbB receptors and differ in their biological activities
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DOI：
10.1074/jbc.271.11.6071
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发表时间：
1996-03-15
影响因子：
4.8
通讯作者：
Hynes, NE
中科院分区：
文献类型：
--
作者：
Beerli, RR;Hynes, NE
已经描述了许多表皮生长因子（EGF）相关肽结合受体酪氨酸激酶的ErbB家族成员。虽然几种EGF激动剂结合并激活ErbB-1/EGF受体，但neu分化因子（NDF）作为ErbB-3和ErbB-4的配体发挥作用。然而，目前还不清楚ErbB受体的哪些特定子集响应于这些配体中的每一个而被激活。本研究使用T47 D乳腺肿瘤细胞系解决了这个问题，该细胞系表达中等水平的所有目前已知的ErbB受体。我们发现，所有的EGF激动剂，但不是NDF，刺激ErbB-1的酪氨酸磷酸化。相反，除了双调蛋白外，所有EGF相关因子都能诱导ErbB-2的酪氨酸磷酸化。诱导ErbB-3酪氨酸磷酸化的能力在不同的EGF相关肽之间变化很大。虽然EGF、转化生长因子（TGF）-α和双调蛋白仅具有中等影响，但NDF显著增加了ErbB-3磷酸酪氨酸含量。最值得注意的是，肝素结合EGF相关生长因子（HB-EGF）和β细胞素（BTC）比其他EGF激动剂更有效。因此，只有NDF，HB-EGF和BTC显着刺激磷脂酰肌醇激酶活性与ErbB-3的关联。在EGF激动剂中，HB-EGF诱导低水平的ErbB-4酪氨酸磷酸化，而BTC在激活ErbB-4方面与NDF一样有效。ErbB-4的BTC活化似乎不依赖于ErbB-1，如用抑制EGF激动剂与ErbB-1结合的抗体预处理细胞所示。由于ErbB受体的差异激活，大多数EGF相关生长因子对培养的乳腺上皮细胞系具有不同的生物活性。
Numerous epidermal growth factor (EGF)-related peptide binding members of the ErbB family of receptor tyrosine kinases have been described. While several EGF agonists bind and activate ErbB-1/EGF receptor, neu differentiation factor (NDF) functions as a ligand for ErbB-3 and ErbB-4. However, it is currently unknown which specific subsets of ErbB receptors become activated in response to each of these ligands. The present study addresses this issue using the T47D breast tumor cell line, which expresses moderate levels of all the presently known ErbB receptors. We show that all the EGF agonists, but not NDF, stimulated tyrosine phosphorylation of ErbB-1. In contrast, all the EGF-related factors except amphiregulin were able to induce tyrosine phosphorylation of ErbB-2. The ability to induce tyrosine phosphorylation of ErbB-3 varied dramatically among the different EGF-related peptides. While EGF, transforming growth factor (TGF)-alpha, and amphiregulin only had a moderate effect, NDF dramatically increased the ErbB-3 phosphotyrosine content. Most notably, heparin binding EGF-related growth factor (HB-EGF) and betacellulin (BTC) were more effective than other EGF agonists. Consequently, only NDF, HB-EGF, and BTC significantly stimulated association of phosphatidylinositol kinase activity with ErbB-3. Among the EGF agonists, HB-EGF induced a low level of ErbB-4 tyrosine phosphorylation, while BTC was as efficient as NDF in activating ErbB-4. The BTC activation of ErbB-4 appears to be independent of ErbB-1, as shown by pretreatment of cells with an antibody that inhibits binding of EGF agonists to ErbB-1. As a result of the differential activation of ErbB receptors, most of the EGF-related growth factors had distinguishable biological activities on cultured mammary epithelial cell lines.