Blanchet Marie-Hélène, Le Good J Ann, Oorschot Viola, Baflast Stéphane, Minchiotti Gabriella, Klumperman Judith, Constam Daniel B
Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Chemin des Boveresses 155, CH 1066 Epalinges, Switzerland.
Sci Signal. 2008 Nov 11;1(45):ra13. doi: 10.1126/scisignal.1165027.
Cripto is a glycosylphosphatidylinositol (GPI)-anchored co-receptor of Nodal and several other transforming growth factor-beta (TGF-beta) family ligands. It contains an epidermal growth factor (EGF)-like motif and a Cripto-FRL1-Cryptic (CFC) domain, which are conserved in a family of EGF-CFC proteins. The EGF domain is thought to recruit Nodal, whereas the CFC domain mediates binding to activin receptor-like kinase 4 (ALK4). We found that the EGF-like motif of Cripto was not essential for its binding to Nodal. However, through residues phenylalanine 78 and glycine 71, Cripto enriched Nodal at the limiting membrane of early endosomes. Similarly, residues in the CFC domain that mediate binding of Cripto to ALK4 were required to attenuate sequestration of Nodal in the endosomal lumen. Thus, we propose that Cripto stimulates Nodal activity by localizing it at the interface of endosomes with cytoplasmic effectors. To our knowledge, Cripto is the first GPI-anchored protein shown to control intraendosomal sorting of its associated cargo.
Cripto是一种糖基磷脂酰肌醇（GPI）锚定的共受体，与Nodal以及其他几种转化生长因子-β（TGF-β）家族配体结合。它包含一个表皮生长因子（EGF）样基序和一个Cripto-FRL1-Cryptic（CFC）结构域，这些在EGF-CFC蛋白家族中是保守的。EGF结构域被认为可招募Nodal，而CFC结构域介导与激活素受体样激酶4（ALK4）的结合。我们发现Cripto的EGF样基序对于其与Nodal的结合并非必需。然而，通过苯丙氨酸78和甘氨酸71残基，Cripto在内体早期的限制膜处富集了Nodal。同样，介导Cripto与ALK4结合的CFC结构域中的残基对于减弱Nodal在内体腔中的隔离是必需的。因此，我们提出Cripto通过将Nodal定位在内体与细胞质效应器的界面来刺激其活性。据我们所知，Cripto是首个被证明可控制其相关货物在内体中分类的GPI锚定蛋白。
