ArticleMolecular and cellular biology2014
The PTH-Gαs-protein kinase A cascade controls αNAC localization to regulate bone mass.
Article in Molecular and cellular biology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 21 citations in OpenAlex.
- Caveolin-1 Regulates Parathyroid Hormone (PTH)-Related Protein (PTHrP) Actions on PTH Receptor Type 1 in Bone Cells.Journal of cellular physiology · 2025Article
- Fracture healing: cellular mechanisms and impact of parathyroid hormone and its analogs.Frontiers in endocrinology · 2025Review
- Review
- Article
- NACA and LRP6 Are Part of a Common Genetic Pathway Necessary for Full Anabolic Response to Intermittent PTH.International journal of molecular sciences · 2022Article
- Expression and Role of Ubiquitin-Specific Peptidases in Osteoblasts.International journal of molecular sciences · 2021Review
- Ubiquitin specific peptidase Usp53 regulates osteoblast versus adipocyte lineage commitment.Scientific reports · 2021Article
- Dephosphorylation of the transcriptional cofactor NACA by the PP1A phosphatase enhances cJUN transcriptional activity and osteoblast differentiation.The Journal of biological chemistry · 2019Article
- Regulation of Bone Remodeling by Parathyroid Hormone.Cold Spring Harbor perspectives in medicine · 2018Review
- Parathyroid Hormone Signaling in Osteocytes.JBMR plus · 2018Review
- Connexin43 and Runx2 Interact to Affect Cortical Bone Geometry, Skeletal Development, and Osteoblast and Osteoclast Function.Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 2017Article
- Heterotrimeric G proteins in the control of parathyroid hormone actions.Journal of molecular endocrinology · 2017Review
- Deficiency of the intermediate filament synemin reduces bone mass in vivo.American journal of physiology. Cell physiology · 2016Article
Corrections and comments
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Authors and funding
8 authors at 4 institutions in 2 countries.
Funding
Abstract
The binding of PTH to its receptor induces Gα(s)-dependent cyclic AMP (cAMP) accumulation to turn on effector kinases, including protein kinase A (PKA). The phenotype of mice with osteoblasts specifically deficient for Gα(s) is mimicked by a mutation leading to cytoplasmic retention of the transcriptional coregulator αNAC, suggesting that Gαs and αNAC form part of a common genetic pathway. We show that treatment of osteoblasts with PTH(1-34) or the PKA-selective activator N(6)-benzoyladenosine cAMP (6Bnz-cAMP) leads to translocation of αNAC to the nucleus. αNAC was phosphorylated by PKA at serine 99 in vitro. Phospho-S99-αNAC accumulated in osteoblasts exposed to PTH(1-34) or 6Bnz-cAMP but not in treated cells expressing dominant-negative PKA. Nuclear accumulation was abrogated by an S99A mutation but enhanced by a phosphomimetic residue (S99D). Chromatin immunoprecipitation (ChIP) analysis showed that PTH(1-34) or 6Bnz-cAMP treatment leads to accumulation of αNAC at the Osteocalcin (Ocn) promoter. Altered gene dosages for Gα(s) and αNAC in compound heterozygous mice result in reduced bone mass, increased numbers of osteocytes, and enhanced expression of Sost. Our results show that αNAC is a substrate of PKA following PTH signaling. This enhances αNAC translocation to the nucleus and leads to its accumulation at target promoters to regulate transcription and affect bone mass.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.