| First Author | Pellicelli M | Year | 2014 |
| Journal | Mol Cell Biol | Volume | 34 |
| Issue | 9 | Pages | 1622-33 |
| PubMed ID | 24550008 | Mgi Jnum | J:213680 |
| Mgi Id | MGI:5585571 | Doi | 10.1128/MCB.01434-13 |
| Citation | Pellicelli M, et al. (2014) The PTH-Galphas-protein kinase A cascade controls alphaNAC localization to regulate bone mass. Mol Cell Biol 34(9):1622-33 |
| abstractText | The binding of PTH to its receptor induces Galpha(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 Galpha(s) is mimicked by a mutation leading to cytoplasmic retention of the transcriptional coregulator alphaNAC, suggesting that Galphas and alphaNAC 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 alphaNAC to the nucleus. alphaNAC was phosphorylated by PKA at serine 99 in vitro. Phospho-S99-alphaNAC 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 alphaNAC at the Osteocalcin (Ocn) promoter. Altered gene dosages for Galpha(s) and alphaNAC in compound heterozygous mice result in reduced bone mass, increased numbers of osteocytes, and enhanced expression of Sost. Our results show that alphaNAC is a substrate of PKA following PTH signaling. This enhances alphaNAC translocation to the nucleus and leads to its accumulation at target promoters to regulate transcription and affect bone mass. |
