Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 38, Pages 10113-10118Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1705755114
Keywords
Smad7; gp130; STAT3; TGF-beta; pluripotency; differentiation
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Funding
- National Natural Science Foundation of China (NSFC) [NSFC 91540205, NSFC 31571447, NSFC 31090360]
- Ministry of Sciences and Technology of China (MOST) [2015CB553800, 2013CB966600]
- Department of Defense [1W81XWH-15-1-0650]
- NIH [R21CA209007, R01AR053591, R01DK073932]
- Fundamental Research Funds for the Central Universities
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Smad7 is a negative feedback product of TGF-beta superfamily signaling and fine tunes a plethora of pleiotropic responses induced by TGF-beta ligands. However, its noncanonical functions independent of TGF-beta 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-beta 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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