Cited by 35Bone Metabolism and DiseasesNF-κB Signaling PathwaysCytokine Signaling Pathways and Interactions

STAC2 negatively regulates osteoclast formation by targeting the RANK signaling complex

Open access
Jeong, Eutteum, Choi, Han Kyoung, Park, Jin Hee, Lee, Soo Young·2018·Cell Death & Differentiation

Abstract

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
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
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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