Cripto-1 indirectly stimulates the tyrosine phosphorylation of erb B-4 through a novel receptor
Cripto-1 indirectly stimulates the tyrosine phosphorylation of erb B-4 through a novel receptor
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DOI：
10.1074/jbc.274.13.8624
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发表时间：
1999-03-26
影响因子：
4.8
通讯作者：
Salomon, DS
中科院分区：
文献类型：
--
作者：
Bianco, C;Kannan, S;Salomon, DS
Cripto-1 (CR-1) 是最近发现的一种表皮生长因子家族蛋白，无法直接与四种已知的 erb B 1 型受体酪氨酸激酶中的任何一种结合。本研究表明，在不同的小鼠和人乳腺上皮细胞系中，CR-1 间接诱导 erb B-4 的酪氨酸磷酸化，但不诱导表皮生长因子相关受体 erb B-2 和 erb B-3 的酪氨酸磷酸化。此外，使用抗 erb B-4 阻断抗体或靶向 erb B-4 mRNA 的锤头核酶载体，在 NMuMG 小鼠乳腺上皮细胞和 T47D 人乳腺癌细胞中下调 erb B-4，会损害 CR-1 完全激活丝裂原激活蛋白激酶的能力。最后，I-125-CR-1 与小鼠和人类乳腺上皮细胞膜的化学交联导致标记出两条分子量分别为 130 和 60 kDa 的特定条带，表明 CR-1 受体代表了一种在结构上与任何已知的 I 型受体酪氨酸激酶无关的新型受体。总之，这些数据表明，CR-1 在与未知受体结合后，可以增强 erb B-4 的酪氨酸激酶活性，并且功能性 erb B-4 受体是 CR-1 诱导的 MAPK 激活所必需的。
Cripto-1 (CR-1) is a recently discovered protein of the epidermal growth factor family that fails to directly bind to any of the four known erb B type 1 receptor tyrosine kinases. The present study demonstrates that CR-1 indirectly induces tyrosine phosphorylation of erb B-4 but not of the epidermal growth factor-related receptors erb B-2 and erb B-3 in different mouse and human mammary epithelial cell lines. In addition, downregulation of erb B-4 in NMuMG mouse mammary epithelial cells and in T47D human breast cancer cells, using an anti-erb B-4 blocking antibody or a hammerhead ribozyme vector targeted to erb B-4 mRNA, impairs the ability of CR-1 to fully activate mitogen-activated protein kinase. Finally, chemical cross-linking of I-125-CR-1 to mouse and human mammary epithelial cell membranes results in the labeling of two specific bands with a molecular weight of 130 and 60 kDa, suggesting that the CR-1 receptor represents a novel receptor structurally unrelated to any of the known type I receptor tyrosine kinases. In conclusion, these data demonstrate that CR-1, upon binding to an unknown receptor, can enhance the tyrosine kinase activity of erb B-4 and that a functional erb B-4 receptor is required for CR-1-induced MAPK activation.