Gray Peter C, Shani Gidi, Aung Kevin, Kelber Jonathan, Vale Wylie
Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Mol Cell Biol. 2006 Dec;26(24):9268-78. doi: 10.1128/MCB.01168-06. Epub 2006 Oct 9.
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, TbetaRI. 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 epithelial 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.
Cripto是一种发育性癌蛋白，属于表皮生长因子-Cripto、FRL-1、Cryptic细胞外信号分子家族。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（包括Nodal、生长分化因子1（GDF1）和GDF3）的必需共受体发挥作用。作为一种癌基因，Cripto被认为通过包括激活有丝分裂信号通路和拮抗激活素信号在内的机制促进肿瘤生长。在这里，我们提供了支持一种新机制的证据，即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TβRI的结合。与其阻断受体组装的能力一致，Cripto在多种细胞类型中抑制TGF-β信号传导，并减弱TGF-β在乳腺上皮细胞中的细胞生长抑制作用。此外，通过使用小干扰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。
