| First Author | Rybchyn MS | Year | 2019 |
| Journal | J Biol Chem | Volume | 294 |
| Issue | 44 | Pages | 16337-16350 |
| PubMed ID | 31527082 | Mgi Jnum | J:283060 |
| Mgi Id | MGI:6383586 | Doi | 10.1074/jbc.RA118.006587 |
| Citation | Rybchyn MS, et al. (2019) Homer1 mediates CaSR-dependent activation of mTOR complex 2 and initiates a novel pathway for AKT-dependent beta-catenin stabilization in osteoblasts. J Biol Chem 294(44):16337-16350 |
| abstractText | The calcium-sensing receptor (CaSR) is critical for skeletal development, but its mechanism of action in osteoblasts is not well-characterized. In the central nervous system (CNS), Homer scaffolding proteins form signaling complexes with two CaSR-related members of the G protein-coupled receptor (GPCR) family C, metabotropic glutamate receptor 1 (mGluR1) and mGluR5. Here, we show that CaSR and Homer1 are co-expressed in mineralized mouse bone and also co-localize in primary human osteoblasts. Co-immunoprecipitation experiments confirmed that Homer1 associates with CaSR in primary human osteoblasts. The CaSR-Homer1 protein complex, whose formation was increased in response to extracellular Ca(2+), was bound to mechanistic target of rapamycin (mTOR) complex 2 (mTORC2), a protein kinase that phosphorylates and activates AKT Ser/Thr kinase (AKT) at Ser(473) siRNA-based gene-silencing assays with primary osteoblasts revealed that both CaSR and Homer1 are required for extracellular Ca(2+)-stimulated AKT phosphorylation and thereby inhibit apoptosis and promote AKT-dependent beta-catenin stabilization and cellular differentiation. To confirm the role of the CaSR-Homer1 complex in AKT initiation, we show that in HEK-293 cells, co-transfection with both Homer1c and CaSR, but neither with Homer1c nor CaSR alone, establishes sensitivity of AKT-Ser(473) phosphorylation to increases in extracellular Ca(2+) concentrations. These findings indicate that Homer1 mediates CaSR-dependent AKT activation via mTORC2 and thereby stabilizes beta-catenin in osteoblasts. |
