EGF MEDIATED SIGNAL TRANSDUCTION THROUGH COEXPRESSED ERBB2 AND ERBB3 RECEPTORS

白细胞介素-3（IL-3）依赖性鼠32 D细胞未检测到 表达表皮生长因子受体（EGFR）， EGF、调蛋白（HRG）或其他已知的EGF样配体。 在这里，我们报告说，EGF特异性结合，并可以交联 共表达ErbB 2和ErbB 3的32 D转染子（32D.E2/E3），但不表达ErbB 2和ErbB 3。 分别表达ErbB 2或ErbB 3的转染子。 在32D.E2/E3细胞中检测到的[125 I]EGF交联物质是 被HRG和β细胞素（BTC）取代，但不被其他EGF样 分析的配体。EGF、BTC和HRG也能诱导受体 酪氨酸磷酸化，下游信号分子的激活 和32D.E2/E3细胞增殖。32 D转染子也被 产生单独表达ErbB 3-EGFR嵌合体（32D.E3-E1）或 与ErbB 2（32D.E2/E3-E1）组合。当HRG刺激32D.E3- E1细胞导致DNA合成和受体磷酸化，EGF和 BTC不活跃。然而，EGF和BTC与HRG一样有效， 当ErbB 2与嵌合体在细胞中共表达时， 32D.E2/E3-E1转染子。这些结果提供了证据， EGF和BTC的ErbB 2/ErbB 3结合位点由先前的 一种未描述的机制，需要两种不同的 受体。使用MDA MB 134人乳腺癌的额外数据 细胞，其在缺乏EGFR的情况下天然表达ErbB 2和ErbB 3， 支持使用32 D细胞获得的结果，并表明EGF 和BTC可能有助于癌的进展， ErbB 2和ErbB 3。

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. [125I]EGF- crosslinked species detected in 32D.E2/E3 cells were displaced by HRG and betacellulin (BTC) but not by other EGF-like ligands that were analyzed. EGF, BTC 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 BTC were inactive. However, EGF and BTC 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 BTC 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 BTC may contribute to the progression of carcinomas that co-express ErbB2 and ErbB3.