Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, Zhejiang 310058, China.
Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030.
Proc Natl Acad Sci U S A. 2017 Sep 19;114(38):10113-10118. doi: 10.1073/pnas.1705755114. Epub 2017 Sep 5.
Smad7 is a negative feedback product of TGF-β superfamily signaling and fine tunes a plethora of pleiotropic responses induced by TGF-β ligands. However, its noncanonical functions independent of TGF-β signaling remain to be elucidated. Here, we show that Smad7 activates signal transducers and activators of transcription 3 (STAT3) signaling in maintaining mouse embryonic stem cell pluripotency in a manner independent of the TGF-β receptors, yet dependent on the leukemia inhibitory factor (LIF) coreceptor glycoprotein 130 (gp130). Smad7 directly binds to the intracellular domain of gp130 and disrupts the SHP2-gp130 or SOCS3-gp130 complex, thereby amplifying STAT3 activation. Consequently, Smad7 facilitates LIF-mediated self-renewal of mouse ESCs and is also critical for induced pluripotent stem cell reprogramming. This finding illustrates an uncovered role of the Smad7-STAT3 interplay in maintaining cell pluripotency and also implicates a mechanism involving Smad7 underlying cytokine-dependent regulation of cancer and inflammation.
Smad7 是 TGF-β 超家族信号的负反馈产物，可精细调节 TGF-β 配体诱导的多种多功能反应。然而，Smad7 独立于 TGF-β 信号的非经典功能仍有待阐明。在这里，我们发现 Smad7 通过一种独立于 TGF-β 受体但依赖于白血病抑制因子（LIF）辅助受体糖蛋白 130（gp130）的方式激活信号转导子和转录激活子 3（STAT3）信号，从而维持小鼠胚胎干细胞的多能性。Smad7 可直接与 gp130 的细胞内结构域结合，并破坏 SHP2-gp130 或 SOCS3-gp130 复合物，从而放大 STAT3 的激活。因此，Smad7 促进了 LIF 介导的小鼠 ESC 的自我更新，对于诱导多能干细胞重编程也至关重要。这一发现说明了 Smad7-STAT3 相互作用在维持细胞多能性方面的一个未被揭示的作用，也暗示了一种涉及 Smad7 的机制，它是细胞因子依赖的癌症和炎症调控的基础。
