SOCS3: an essential regulator of LIF receptor signaling in trophoblast giant cell differentiation
Open accessAbstract
Suppressor of cytokine signaling 3 (SOCS3) binds cytokine receptors and thereby suppresses cytokine signaling. Deletion of SOCS3 causes an embryonic lethality that is rescued by a tetraploid rescue approach, demonstrating an essential role in placental development and a non-essential role in embryo development. Rescued SOCS3-deficient mice show a perinatal lethality with cardiac hypertrophy. SOCS3-deficient placentas have reduced spongiotrophoblasts and increased trophoblast secondary giant cells. Enforced expression of SOCS3 in a trophoblast stem cell line (Rcho-1) suppresses giant cell differentiation. Conversely, SOCS3-deficient trophoblast stem cells differentiate more readily to giant cells in culture, demonstrating that SOCS3 negatively regulates trophoblast giant cell differentiation. Leukemia inhibitory factor (LIF) promotes giant cell differentiation in vitro, and LIF receptor (LIFR) deficiency results in loss of giant cell differentiation in vivo. Finally, LIFR deficiency rescues the SOCS3-deficient placental defect and embryonic lethality. The results establish SOCS3 as an essential regulator of LIFR signaling in trophoblast differentiation.
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Each of these stimuli activates the glycoprotein-130/STAT3 or G-CSF-receptor/STAT3 signaling pathways, which are known to be inhibited by SOCS3 in vivo.
“Interestingly, each of these stimuli activates the glycoprotein-130/STAT3 or the granulocytecolony stimulating factor-receptor/STAT3 signaling pathways, which are known to be inhibited by SOCS3 in vivo (24 -26, 29, 40, 41).”
From The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling (2006) · cites this paper as [40]
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Wormald, S., Zhang, J.-G., Krebs, D. L., Mielke, L. A., Silver, J., Alexander, W. S., Speed, T. P., Nicola, N. A., & Hilton, D. J. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m509595200 · Cited by 123 · see citing works
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Structural Basis for Phosphotyrosine Recognition by Suppressor of Cytokine Signaling-3
Bergamin, E., Wu, J., & Hubbard, S. R. (2006) · Structure · doi:10.1016/j.str.2006.06.011 · Cited by 60 · see citing works
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- Authors
- Takahashi, Y., Carpino, N., Cross, J. C., Torres, M., Parganas, E., & Ihle, J. N.
- Affiliations
- St. Jude Children's Research Hospital (US)
- University of Calgary (CA)
- Centro Nacional de Biotecnología (ES)
- Corresponding author
- Ihle, James N.
- ORCID
- Takahashi, Yutaka
- Venue
- The EMBO Journal
- Published
- 2003-02-03
- Volume
- 22
- Issue
- 3
- Pages
- 372-384
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC140741
- OpenAlex
- W1967258978
- Cited by
- 208
- References
- 1
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 5 · 2023: 4 · 2022: 3 · 2021: 6 · 2020: 4 · 2019: 3 · 2018: 4 · 2017: 7 · 2016: 2 · 2015: 10 · 2014: 5 · 2013: 13 · 2012: 11
- FWCI
- 10.17
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Immunology and Microbiology › Immunology › Reproductive System and Pregnancy
- Health Sciences › Medicine › Obstetrics and Gynecology › Pregnancy and preeclampsia studies
- Keywords
- SOCS3, leukemia inhibitory factor, LIF receptor, spongiotrophoblast, placental development, trophoblast stem cells, cardiac hypertrophy, embryonic lethality
- MeSH terms
- Suppressor of Cytokine Signaling 3 Protein, Animals, Cell Differentiation, Cell Line, Embryo, Mammalian, Gestational Age, Myocardium, Placenta, Proteins, Repressor Proteins, Stem Cells, Tissue Distribution, Transcription Factors, Trophoblasts, Signal Transduction, Survival Rate, In Situ Hybridization, Receptors, Cytokine, Mice, Knockout, Cell Lineage, Suppressor of Cytokine Signaling Proteins, Mice, Receptors, OSM-LIF, Leukemia Inhibitory Factor Receptor alpha Subunit
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