From the Department of Experimental Pathology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575.
J Biol Chem. 2014 May 2;289(18):12680-92. doi: 10.1074/jbc.M114.558981. Epub 2014 Mar 13.
Transforming growth factor (TGF)-β signaling is deliberately regulated at multiple steps in its pathway from the extracellular microenvironment to the nucleus. However, how TGF-β signaling is activated or attenuated is not fully understood. We recently identified transmembrane prostate androgen-induced RNA (TMEPAI), which is involved in a negative feedback loop of TGF-β signaling. When we searched for a family molecule(s) for TMEPAI, we found C18ORF1, which, like TMEPAI, possesses two PY motifs and one Smad-interacting motif (SIM) domain. As expected, C18ORF1 could block TGF-β signaling but not bone morphogenetic protein signaling. C18ORF1 bound to Smad2/3 via its SIM and competed with the Smad anchor for receptor activation for Smad2/3 binding to attenuate recruitment of Smad2/3 to the TGF-β type I receptor (also termed activin receptor-like kinase 5 (ALK5)), in a similar fashion to TMEPAI. Knockdown of C18ORF1 prolonged duration of TGF-β-induced Smad2 phosphorylation and concomitantly potentiated the expression of JunB, p21, and TMEPAI mRNAs induced by TGF-β. Consistently, TGF-β-induced cell migration was enhanced by the knockdown of C18ORF1. These results indicate that the inhibitory function of C18ORF1 on TGF-β signaling is similar to that of TMEPAI. However, in contrast to TMEPAI, C18ORF1 was not induced upon TGF-β signaling. Thus, we defined C18ORF1 as a surveillant of steady state TGF-β signaling, whereas TMEPAI might help C18ORF1 to inhibit TGF-β signaling in a coordinated manner when cells are stimulated with high levels of TGF-β.
转化生长因子 (TGF)-β 信号通路从细胞外微环境到细胞核的多个步骤都受到精心调控。然而，TGF-β 信号的激活或衰减机制尚不完全清楚。我们最近发现了跨膜前列腺雄激素诱导 RNA（TMEPAI），它参与 TGF-β 信号的负反馈回路。在寻找 TMEPAI 的家族分子时，我们发现了 C18ORF1，它与 TMEPAI 一样，具有两个 PY 基序和一个 Smad 相互作用基序（SIM）结构域。正如预期的那样，C18ORF1 可以阻断 TGF-β 信号，但不能阻断骨形态发生蛋白信号。C18ORF1 通过其 SIM 与 Smad2/3 结合，并与 Smad 锚竞争受体激活，从而阻止 Smad2/3 与 TGF-β 型 I 受体（也称为激活素受体样激酶 5（ALK5））结合，从而减弱 Smad2/3 向 TGF-β 型 I 受体的募集，这种方式类似于 TMEPAI。C18ORF1 的敲低延长了 TGF-β 诱导的 Smad2 磷酸化的持续时间，并协同增强了 TGF-β 诱导的 JunB、p21 和 TMEPAI mRNA 的表达。一致地，C18ORF1 的敲低增强了 TGF-β 诱导的细胞迁移。这些结果表明，C18ORF1 对 TGF-β 信号的抑制作用与 TMEPAI 相似。然而，与 TMEPAI 不同，C18ORF1 不会在 TGF-β 信号诱导时被诱导。因此，我们将 C18ORF1 定义为 TGF-β 信号稳态的监测者，而 TMEPAI 可能有助于 C18ORF1 在细胞受到高水平 TGF-β 刺激时协调抑制 TGF-β 信号。
