Cripto-1 activates nodal- and ALK4-dependent and -independent signaling pathways in mammary epithelial cells
Cripto-1 activates nodal- and ALK4-dependent and -independent signaling pathways in mammary epithelial cells
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DOI：
10.1128/mcb.22.8.2586-2597.2002
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发表时间：
2002-04-01
影响因子：
5.3
通讯作者：
Salomon, DS
中科院分区：
文献类型：
--
作者：
Bianco, C;Adkins, HB;Salomon, DS
Cripto-1（CR-1）是表皮生长因子CFC（EGF-CFC）家族成员，在胚胎发生和乳腺发育中具有已证实的作用，并在几种人类肿瘤中过表达。最近，EGF-CFC蛋白被认为是Nodal的必需信号传导辅因子，Nodal是一种转化生长因子β家族成员，其表达先前被定义为胚胎特异性的。为了鉴定CR-1的受体，以CR-1蛋白为诱饵筛选人脑cDNA噬菌体展示文库。鉴定了与ALK 4（激活素的I型丝氨酸/苏氨酸激酶受体）具有同一性的噬菌体插入物。在荧光激活细胞分选仪分析中以及通过免疫共沉淀，CR-1与哺乳动物上皮细胞上表达的细胞表面ALK 4结合。Nodal在乳腺中与小鼠Cr-1共表达，并且CR-1仅在Nodal和ALK 4存在下才能磷酸化EPH-4乳腺上皮细胞中的转录因子Smad-2。相比之下，CR-1刺激这些细胞中的促分裂原活化蛋白激酶和AKT不依赖于Nodal和ALK 4，这表明CR-1可能调节不同的信号通路以介导其不同的功能作用。
Cripto-1 (CR-1), an epidermal growth factor-CFC (EGF-CFC) family member, has a demonstrated role in embryogenesis and mammary gland development and is overexpressed in several human tumors. Recently, EGF-CFC proteins were implicated as essential signaling cofactors for Nodal, a transforming growth factor beta family member whose expression has previously been defined as embryo specific. To identify a receptor for CR-1, a human brain cDNA phage display library was screened using CR-1 protein as bait. Phage inserts with identity to ALK4, a type I serine/threonine kinase receptor for Activin, were identified. CR-1 binds to cell surface ALK4 expressed on mammalian epithelial cells in fluorescence-activated cell sorter analysis, as well as by coimmunoprecipitation. Nodal is coexpressed with mouse Cr-1 in the mammary gland, and CR-1 can phosphorylate the transcription factor Smad-2 in EpH-4 mammary epithelial cells only in the presence of Nodal and ALK4. In contrast, CR-1 stimulation of mitogen-activated protein kinase and AKT in these cells is independent of Nodal and ALK4, suggesting that CR-1 may modulate different signaling pathways to mediate its different functional roles.