Epidermal growth factor and betacellulin mediate signal transduction through co-expressed ErbB2 and ErbB3 receptors
Epidermal growth factor and betacellulin mediate signal transduction through co-expressed ErbB2 and ErbB3 receptors
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DOI：
10.1093/emboj/16.18.5608
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发表时间：
1997-09-15
期刊：
影响因子：
11.4
通讯作者：
Pierce, JH
中科院分区：
文献类型：
--
作者：
Alimandi, M;Wang, LM;Pierce, JH
白介素3(IL-3)依赖的小鼠32D细胞不表达表皮生长因子受体(EGFR)，也不能对EGF、Hereglin(HRG)或其他已知的EGF样配体产生反应而增殖，在此，我们报道EGF与共表达ErbB2和ErbB3的32D转染体(32D.E2/E3)特异性结合并可与其交联，但不能与单独表达ErbB2或ErbB3的转染体结合。[I-125]在32D.E2/E3细胞中检测到的EGF交联物被HRG和β-细胞蛋白(ETC)取代，但不被所分析的其他EGF样配体取代。EGF、ETC和HRG还可诱导受体酪氨酸磷酸化，激活下游信号分子，促进32D.E2/E3细胞增殖。此外，还获得了单独表达ErbB3-EGFR嵌合体(32D.E3-E1)或与ErbB2联合表达(32D.E2/E3-E1)的32D转基因细胞。32D.E3-E1细胞经HRG刺激后，DNA合成和受体磷酸化，EGF等失活。然而，当ErbB2与32D.E2/E3-E1中的嵌合体共表达时，EGF和ETC在介导信号转导方面与HRG一样有效。这些结果提供了证据，证明EGF和ETC的ErbB2/ErbB3结合位点是由先前未描述的机制形成的，需要两个不同的受体共同表达。利用MDA MB134人乳腺癌细胞(在没有EGFR的情况下自然表达ErbB2和ErbB3)的额外数据支持使用32D细胞获得的结果，并表明EGF和ETC可能有助于共同表达ErbB2和ErbB3的癌症的进展。
Interleukin-3 (IL-3)-dependent murine 32D cells do not detectably express epidermal growth factor receptors (EGFRs) and do not proliferate in response to EGF, heregulin (HRG) or other known EGF-like ligands, Here, we report that EGF specifically binds to and can be crosslinked to 32D transfectants co-expressing ErbB2 and ErbB3 (32D.E2/E3), but not to transfectants expressing either ErbB2 or ErbB3 individually. [I-125]EGF-crosslinked species detected in 32D.E2/E3 cells were displaced by HRG and betacellulin (ETC) but not by other EGF-like ligands that were analyzed. EGF, ETC and HRG also induced receptor tyrosine phosphorylation, activation of downstream signaling molecules and proliferation of 32D.E2/E3 cells. 32D transfectants were also generated which expressed an ErbB3-EGFR chimera alone (32D.E3-E1) or in combination with ErbB2 (32D.E2/E3-E1). While HRG stimulation of 32D.E3-E1 cells resulted in DNA synthesis and receptor phosphorylation, EGF and ETC were inactive. However, EGF and ETC were as effective as HRG in mediating signaling when ErbB2 was co-expressed with the chimera in the 32D.E2/E3-E1 transfectant. These results provide evidence that ErbB2/ErbB3 binding sites for EGF and ETC are formed by a previously undescribed mechanism that requires co-expression of two distinct receptors. Additional data utilizing MDA MB134 human breast carcinoma cells, which naturally express ErbB2 and ErbB3 in the absence of EGFRs, supported the results obtained employing 32D cells and suggest that EGF and ETC may contribute to the progression of carcinomas that co-express ErbB2 and ErbB3.