Cripto binds transforming growth factor β (TGF-β) and inhibits TGF-β signaling
Cripto binds transforming growth factor β (TGF-β) and inhibits TGF-β signaling
复制标题
DOI：
10.1128/mcb.01168-06
复制
发表时间：
2006-12-01
影响因子：
5.3
通讯作者：
Vale, Wylie
中科院分区：
文献类型：
--
作者：
Gray, Peter C.;Shani, Gidi;Vale, Wylie
Cripto是一种发育癌蛋白，是表皮生长因子Cripto，FRL-1，细胞外信号分子隐藏家族的成员。除了在胚胎发生过程中具有重要功能外，Cripto在肿瘤中高度表达并促进肿瘤发生。在发育过程中，Cripto作为转化生长因子β（TGF-β）配体的专性辅助受体，包括α 1、生长和分化因子1（GDF 1）和GDF 3。作为一种致癌基因，Cripto被认为通过包括促有丝分裂信号传导途径的激活和激活素信号传导的拮抗的机制促进肿瘤生长。在这里，我们提供的证据支持一种新的机制，其中Cripto抑制TGF-β的肿瘤抑制功能。Cripto结合TGF-β并减少TGF-β与其I型受体T β RI的结合。与其阻断受体组装的能力一致，Cripto抑制了多种细胞类型中的TGF-β信号传导，并减弱了TGF-β在乳腺上皮细胞中的细胞生长抑制作用。此外，通过使用小抑制性RNA靶向破坏Cripto表达增强了TGF-β信号传导，表明内源性Cripto在抑制TGF-β反应中起作用。
Cripto is a developmental oncoprotein and a member of the epidermal growth factor-Cripto, FRL-1, Cryptic family of extracellular signaling molecules. In addition to having essential functions during embryogenesis, Cripto is highly expressed in tumors and promotes tumorigenesis. During development, Cripto acts as an obligate coreceptor for transforming growth factor beta (TGF-beta) ligands, including nodals, growth and differentiation factor 1 (GDF1), and GDF3. As an oncogene, Cripto is thought to promote tumor growth via mechanisms including activation of mitogenic signaling pathways and antagonism of activin signaling. Here, we provide evidence supporting a novel mechanism in which Cripto inhibits the tumor suppressor function of TGF-beta. Cripto bound TGF-beta and reduced the association of TGF-beta with its type I receptor, T beta RI. Consistent with its ability to block receptor assembly, Cripto suppressed TGF-beta signaling in multiple cell types and diminished the cytostatic effects of TGF-beta in mammary epitheliall cells. Furthermore, targeted disruption of Cripto expression by use of small inhibitory RNA enhanced TGF-beta signaling, indicating that endogenous Cripto plays a role in restraining TGF-beta responses.