The Actin-Binding Protein PPP1r18 Regulates Maturation, Actin Organization, and Bone Resorption Activity of Osteoclasts
Open accessAbstract
Osteoclasts resorb bone by attaching on the bone matrix and forming a sealing zone. In Src-deficient mice, osteoclasts cannot form the actin ring, a characteristic actin structure that seals the resorbed area, and resorb hardly any bone as a result. However, the molecular mechanism underlying the role of Src in the regulation and organization of the actin ring is still unclear. We identified an actin-regulatory protein, protein phosphatase 1 regulatory subunit 18 (PPP1r18), as an Src-binding protein in an Src-, Yes-, and Fyn-deficient fibroblast (SYF) cell line overexpressing a constitutively active form of Src. PPP1r18 was localized in the nucleus and actin ring. PPP1r18 overexpression in osteoclasts inhibited terminal differentiation, actin ring formation, and bone-resorbing activity. A mutation of the protein phosphatase 1 (PP1)-binding domain of PPP1r18 rescued these phenotypes. In contrast, PPP1r18 knockdown promoted terminal differentiation and actin ring formation. In summary, we showed that PPP1r18 likely plays a role in podosome organization and bone resorption.
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“Based on existing literature, we hypothesize that PPP1R18 may function as a scaffold protein to facilitate Src-mediated activation of the ERK pathway, given that PPP1R18 is a known binding partner of Src, a classic upstream activator of the Ras/Raf/MEK/ERK cascade [18, 21, 38–40].”
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- Authors
- Matsubara, T., Kokabu, S., Nakatomi, C., Kinbara, M., Maeda, T., Yoshizawa, M., Yasuda, H., Takano-Yamamoto, T., Baron, R., & Jimi, E.
- Affiliations
- Kyushu Dental University (JP)
- Tohoku University (JP)
- Oriental Yeast Co., Ltd. (Japan) (JP)
- Department of Orthodontics and Dentofacial Orthopedics, Graduate School of Dentistry, Tohoku University
- Harvard University (US)
- Kyushu University (JP)
- Corresponding author
- Matsubara, Takuma
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2018-02-01
- Volume
- 38
- Issue
- 4
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC5789032
- OpenAlex
- W2768779521
- Cited by
- 28
- References
- 50
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 5 · 2023: 3 · 2022: 6 · 2021: 3 · 2019: 6
- FWCI
- 0.67
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular and Cellular Biology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS | National Institutes of Health (R01 AR062054)
- Ministry of Education, Culture, Sports, Science and Technology (25670870, 16K20423, 23249085, 26293396)
- Fukuoka Foundation for Sound Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Health Sciences › Medicine › Rheumatology › Bone and Dental Protein Studies
- Health Sciences › Medicine › Rheumatology › Osteomyelitis and Bone Disorders Research
- Keywords
- osteoclasts, bone resorption, actin rings, actin organization, podosomes, Src family kinases, osteoclastogenesis, sealing zone
- MeSH terms
- Actins, Animals, Bone Resorption, Cell Adhesion, Cell Differentiation, Cell Line, Humans, Male, Mice, Transgenic, Osteoclasts, Protein Binding, Protein-Tyrosine Kinases, Receptors, Neuropeptide Y, src-Family Kinases, Mice, Dopamine and cAMP-Regulated Phosphoprotein 32, Protein Phosphatase 1
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