3 years ago

Smad7 enables STAT3 activation and promotes pluripotency independent of TGF-{beta} signaling [Cell Biology]

Smad7 enables STAT3 activation and promotes pluripotency independent of TGF-{beta} signaling [Cell Biology]
Bin Zhao, Wenjian Li, Jun Qin, Mu Xiao, Chuang Sun, Pinglong Xu, Zongping Xia, Xia Lin, Yi Yu, Ye-Guang Chen, Sheng Ye, Chen Ding, Shuchen Gu, Lei Wang, Ye Li, Xin-Hua Feng, Yi Li, Dewei Xu, Fenfang Chen

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.

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