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Cited by 47TGF-β signaling in diseasesDevelopmental Biology and Gene RegulationWnt/β-catenin signaling in development and cancer

SMAD4 Feedback Activates the Canonical TGF-β Family Signaling Pathways

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Liu, Lu, Li, Qiqi, Yang, Liu, Li, Qifa, Du, Xing·2021·International Journal of Molecular Sciences
DOI 10.3390/ijms221810024PMC PMC8471547
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Abstract

TGF-β family signaling pathways, including TGF-β and BMP pathways, are widely involved in the regulation of health and diseases through downstream SMADs, which are also regulated by multiple validated mechanisms, such as genetic regulation, epigenetic regulation, and feedback regulation. However, it is still unclear whether R-SMADs or Co-SMAD can feedback regulate the TGF-β family signaling pathways in granulosa cells (GCs). In this study, we report a novel mechanism underlying the feedback regulation of TGF-β family signaling pathways, i.e., SMAD4, the only Co-SMAD, positive feedback activates the TGF-β family signaling pathways in GCs with a basal level of TGF-β ligands by interacting with the core promoters of its upstream receptors. Mechanistically, SMAD4 acts as a transcription factor, and feedback activates the transcription of its upstream receptors, including ACVR1B, BMPR2, and TGFBR2, of the canonical TGF-β signaling pathways by interacting with three coactivators (c-JUN, CREB1, and SP1), respectively. Notably, three different interaction modes between SMAD4 and coactivators were identified in SMAD4-mediated feedback regulation of upstream receptors through reciprocal ChIP assays. Our findings in the present study indicate for the first time that SMAD4 feedback activates the canonical TGF-β family signaling pathways in GCs, which improves and expands the regulatory mechanism, especially the feedback regulation modes of TGF-β family signaling pathways in ovarian GCs.

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  • SMAD4 engages in a feedback loop by activating transcription of its upstream receptors, maintaining pathway sensitivity.

    “Moreover, SMAD4 engages in a feedback loop by activating the transcription of its upstream receptors, thus maintaining pathway sensitivity [62].”

    From Significance of TP53, CDKN2A, SMAD4 and KRAS in Pancreatic Cancer (2024) · cites this paper as [62]

    The Results (§2.2 and §2.5; no page numbers in our copy) show that SMAD4 induces transcription of its upstream receptors, and the Conclusions describe this as positive feedback that activates TGF-β family signaling in porcine granulosa cells. The paper does not establish that this feedback maintains pathway sensitivity, so that consequence goes beyond the reported finding. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • SMAD4 facilitates activation of receptor-regulated SMADs (R-SMADs), including SMAD3 and SMAD1.

    “This multifunctional protein also facilitates the activation of receptor-regulated SMADs (R-SMADs), including SMAD3 and SMAD1, highlighting its role in orchestrating downstream events [62,81].”

    From Significance of TP53, CDKN2A, SMAD4 and KRAS in Pancreatic Cancer (2024) · cites this paper as [62]

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Cited by

Sorted by citations

Authors
Liu, L., Li, Q., Yang, L., Li, Q., & Du, X.
Affiliations
Nanjing Agricultural University (CN)
Corresponding author
Du, Xing
ORCID
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2021-09-16
Volume
22
Issue
18
Pages
10024
ISSN
1422-0067 (ISSN-L)
DOI
10.3390/ijms221810024
PMC
PMC8471547
OpenAlex
W3121311652
Cited by
47
References
2
Citations by year
2026: 6 · 2025: 4 · 2024: 28 · 2023: 4 · 2022: 5
FWCI
2.98
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China (31772568, 31902130)
  • Qinglan Project of Jiangsu Province of China (2020)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
Keywords
SMAD4, feedback regulation, TGF-beta signaling, BMP signaling, granulosa cells, ACVR1B, BMPR2, TGFBR2, transcriptional coactivator, c-Jun, CREB1, Sp1, transcriptional regulation, ovarian follicles
MeSH terms
Receptor, Transforming Growth Factor-beta Type II, Animals, Female, Humans, Ovary, Promoter Regions, Genetic, Blotting, Western, Signal Transduction, Transforming Growth Factor beta, Apoptosis, Computational Biology, Activin Receptors, Type I, Epigenesis, Genetic, Chromatin Immunoprecipitation, Immunoprecipitation, Smad4 Protein, Bone Morphogenetic Protein Receptors, Type II, Real-Time Polymerase Chain Reaction

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