STAC2 negatively regulates osteoclast formation by targeting the RANK signaling complex
Open accessAbstract
The receptor activator of nuclear factor-κB (RANK) protein activates various protein kinase signaling cascades, including those involving NF-κB, mitogen-activated protein kinase (MAPK), and Bruton tyrosine kinase (Btk)/tyrosine-protein kinase Tec. However, the mechanism underlying the negative regulation of RANK by downstream signaling molecules remains unclear. Here, we report that Src homology 3 domain and cysteine-rich domain-containing protein 2 (STAC2) is a novel RANK ligand-inducible protein that negatively regulates RANK-mediated osteoclast formation. STAC2 physically interacts with RANK and inhibits the formation of the RANK signaling complex, which contains Grb-2-associated binder 2 (Gab2) and phospholipase Cγ2 (PLCγ2), thus leading to the suppression of RANK-mediated NF-κB and MAPK activation. Furthermore, STAC2 overexpression limits Btk/Tec-mediated PLCγ2 phosphorylation via the interaction between STAC2 and Btk/Tec. Taken together, our results reveal a novel mechanism whereby RANK signaling is restricted by its physical interaction with STAC2.
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RANKL-dependent pathways activated by pro-inflammatory cytokines can induce osteoclast formation and enhance osteoclast activity.
“RANKL-dependent pathways activated by pro-inflammatory cytokines can induce osteoclast formation, therefore, enhancing osteoclast activity [87, 88].”
From Modulation of fracture healing by senescence-associated secretory phenotype (SASP): a narrative review of the current literature (2024) · cites this paper as [87]
The Introduction states that RANKL–RANK signaling influences osteoclast formation and resorptive activity. It does not say that pro-inflammatory cytokines activate those RANKL-dependent pathways, so that part of the claim is unsupported. (LLM, conf=0.86)
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- Authors
- Jeong, E., Choi, H. K., Park, J. H., & Lee, S. Y.
- Affiliations
- Ewha Womans University (KR)
- Corresponding author
- Lee, Soo Young
- Venue
- Cell Death & Differentiation
- Published
- 2018-01-18
- Volume
- 25
- Issue
- 8
- Pages
- 1364-1374
- ISSN
- 1350-9047 (ISSN-L)
- 1476-5403
- PMC
- PMC6113229
- OpenAlex
- W2793742519
- Cited by
- 35
- References
- 46
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 5 · 2023: 3 · 2022: 4 · 2021: 10 · 2020: 6 · 2018: 3
- FWCI
- 1.69
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Cell Death and Differentiation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Research Foundation (2012R1A5A1048236)
- Ministry of Science, ICT and Future Planning (2012R1A5A1048236)
- National Research Foundation of Korea (2012R1A5A1048236, 2016R1A2B3010699)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Keywords
- RANK signaling, osteoclastogenesis, RANK ligand, Gab2, PLCγ2, NF-κB activation, MAPK activation, Bruton's tyrosine kinase, Tec kinase, negative regulation of signaling, protein-protein interaction
- MeSH terms
- Agammaglobulinaemia Tyrosine Kinase, Animals, Bone Marrow Cells, Cell Differentiation, Mice, Inbred C57BL, Nerve Tissue Proteins, Osteoclasts, Osteogenesis, Phosphoproteins, Phosphorylation, Protein Binding, Protein-Tyrosine Kinases, Signal Transduction, Macrophage Colony-Stimulating Factor, RNA Interference, RNA, Small Interfering, Adaptor Proteins, Signal Transducing, Mice, Phospholipase C gamma, RANK Ligand, Receptor Activator of Nuclear Factor-kappa B
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