New Ligand Binding Function of Human Cerberus and Role of Proteolytic Processing in Regulating Ligand-Receptor Interactions and Antagonist Activity.
New Ligand Binding Function of Human Cerberus and Role of Proteolytic Processing in Regulating Ligand-Receptor Interactions and Antagonist Activity.
复制标题
人 Cerberus 的新配体结合功能以及蛋白水解加工在调节配体-受体相互作用和拮抗剂活性中的作用。
DOI：
10.1016/j.jmb.2016.01.011
复制
发表时间：
2016-02-13
影响因子：
5.6
通讯作者：
Martinez-Hackert E
中科院分区：
文献类型：
--
作者：
Aykul S;Martinez-Hackert E
Cerberus是脊椎动物胚胎发生的关键调节因子。其生物学功能已在青蛙和小鼠胚胎中进行了广泛的研究。其结合和拮抗转化生长因子-β（TGF-β）家族配体Nodal的能力已得到充分证实。引人注目的是，Cerberus的分子功能仍然知之甚少。根本原因是Cerberus是一种复杂的多功能蛋白质：它结合并抑制多种TGF-β家族配体，它可能结合并抑制一些Wnt家族成员，并且已经描述了具有不同活性的两种不同形式。此外，青蛙和哺乳动物Cerberus之间的序列同源性很低，这表明以前的研究，分析青蛙Cerberus的功能，可能无法准确地描述哺乳动物Cerberus的功能。因此，我们着手确定人Cerberus在TGF-β家族信号传导中的分子活性。使用纯化的蛋白质、表面等离子体共振和报告基因测定，我们发现人Cerberus结合并抑制TGF-β家族配体激活素B、BMP-6和BMP-7，但不结合并抑制青蛙Cerberus配体BMP-2。值得注意的是，全长Cerberus成功地阻断了配体与II型受体的结合，但短形式的效果较差。此外，全长Cerberus抑制了乳腺癌细胞的迁移，而短型则没有。因此，我们的研究结果扩展了Cerberus作为TGF-β家族信号传导抑制剂的作用，为N端区域的功能提供了分子理论基础，并支持Cerberus可能具有直接抑制TGF-β家族信号传导以外的调节活性的想法。
Cerberus is a key regulator of vertebrate embryogenesis. Its biological function has been studied extensively in frog and mouse embryos. Its ability to bind and antagonize the transforming growth factor-β (TGF-β) family ligand Nodal is well established. Strikingly, the molecular function of Cerberus remains poorly understood. The underlying reason is that Cerberus is a complex, multifunctional protein: It binds and inhibits multiple TGF-β family ligands, it may bind and inhibit some Wnt family members, and two different forms with distinct activities have been described. In addition, sequence homology between frog and mammalian Cerberus is low, suggesting that previous studies, which analyzed frog Cerberus function, may not accurately describe the function of mammalian Cerberus. We therefore undertook to determine the molecular activities of human Cerberus in TGF-β family signaling. Using purified proteins, surface plasmon resonance, and reporter gene assays, we discovered that human Cerberus bound and inhibited the TGF-β family ligands Activin B, BMP-6, and BMP-7, but not the frog Cerberus ligand BMP-2. Notably, full-length Cerberus successfully blocked ligand binding to type II receptors, but the short form was less effective. In addition, full-length Cerberus suppressed breast cancer cell migration but the short form did not. Thus, our findings expand the roles of Cerberus as TGF-β family signaling inhibitor, provide a molecular rationale for the function of the N-terminal region, and support the idea that Cerberus could have regulatory activities beyond direct inhibition of TGF-β family signaling.
登录
查看更多内容
影响因子：
64.8
作者：
Bouwmeester, T;Kim, SH;DeRobertis, EM
通讯作者：
DeRobertis, EM
影响因子：
10.5
作者：
Cai W;Albini S;Wei K;Willems E;Guzzo RM;Tsuda M;Giordani L;Spiering S;Kurian L;Yeo GW;Puri PL;Mercola M
通讯作者：
Mercola M
DOI：
10.1073/pnas.0711263105
发表时间：
2008-05-13
影响因子：
11.1
作者：
Pearsall, R. Scott;Canalis, Ernesto;Bouxsein, Mary L.
通讯作者：
Bouxsein, Mary L.
影响因子：
11.8
作者：
Perea-Gomez, A;Vella, FDJ;Ang, SL
通讯作者：
Ang, SL
通过循环癌细胞自种肿瘤自种。
影响因子：
64.5
作者：
Kim MY;Oskarsson T;Acharyya S;Nguyen DX;Zhang XH;Norton L;Massagué J
通讯作者：
Massagué J