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Updated: Oct 18, 2025

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SMAD4 Feedback Activates the Canonical TGF-β Family Signaling Pathways

Lu Liu1, Qiqi Li1, Liu Yang1

  • 1College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China.

International Journal of Molecular Sciences
|September 28, 2021
PubMed

Insights

SMAD4, a co-SMAD protein, was found to positively feedback and activate TGF-β signaling in ovarian granulosa cells. This discovery reveals a new regulatory mechanism for TGF-β pathways in these cells.

Area of Science:

  • Cellular signaling pathways
  • Molecular biology
  • Reproductive biology

Background:

  • Transforming growth factor-beta (TGF-β) and bone morphogenetic protein (BMP) pathways regulate vital cellular processes.
  • These pathways involve SMAD proteins, but feedback regulation by SMADs in granulosa cells remains unclear.

Purpose of the Study:

  • To investigate the role of SMAD4, a co-SMAD, in the feedback regulation of TGF-β family signaling pathways in granulosa cells (GCs).

Main Methods:

  • Reciprocal Chromatin Immunoprecipitation (ChIP) assays were employed.
  • Analysis focused on the interaction of SMAD4 with coactivators and upstream receptor gene promoters.

Main Results:

  • SMAD4 was identified as a positive feedback regulator of TGF-β signaling in GCs.
  • SMAD4 interacts with coactivators c-JUN, CREB1, and SP1 to activate transcription of receptors ACVR1B, BMPR2, and TGFBR2.
  • Three distinct interaction modes between SMAD4 and coactivators were characterized.

Conclusions:

  • SMAD4 feedback activates canonical TGF-β family signaling in ovarian granulosa cells.
  • This finding expands the understanding of regulatory mechanisms, particularly feedback loops, in TGF-β signaling within GCs.
Keywords:
RNA sequencingSMAD4TGF-β family signaling pathwaysfeedback regulationgranulosa cellspigtranscriptome

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