title: PTEN regulation by the Akt/GSK-3β axis during RANKL signaling.
abstract: Phosphatase and tensin homolog (PTEN) negatively regulates phosphoinositide 3-kinase (PI3K)/Akt signaling as a lipid phosphatase for the second messenger phosphatidylinositol 3,4,5-triphosphate. We discovered recently that inactivating glycogen synthase kinase-3β (GSK-3β) via Akt plays an important role in receptor activator of nuclear factor κb ligand (RANKL)-induced osteoclastogenesis. However, the signaling link between GSK-3β and PTEN in RANKL signaling has not been revealed. Downregulating PTEN by RNA interference increases Akt and GSK-3β phosphorylation levels by RANKL, thereby promoting the formation of osteoclasts. PTEN phosphorylation at threonine 366 (T366) decreased gradually during RANKL-induced osteoclastogenesis, whereas PTEN protein levels were unaffected. Interestingly, the PTEN phosphorylation defective mutant (T366A) showed increased osteoclastogenesis, which is consistent with its lower phosphatase activity, compared to that of wild-type PTEN. Moreover, treatment with the GSK-3 inhibitor SB216763 suppressed PTEN phosphorylation levels and phosphatase activity and enhanced Akt phosphorylation. These data suggest that inhibiting GSK-3β during RANKL-induced osteoclastogenesis decreases PTEN phosphorylation, leading to enhanced osteoclast differentiation through Akt activation.
authors: Division of Life and Pharmaceutical Sciences, Center for Cell Signaling & Drug Discovery Research, Ewha Womans University, Seoul, South Korea.
authors: Hyun Duk
authors: HD
authors: Jang
authors: Ji Yeon
authors: JY
authors: Noh
authors: Ji Hye
authors: JH
authors: Shin
authors: Jing Jing
authors: JJ
authors: Lin
authors: Soo Young
authors: SY
authors: Lee
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D015536:Down-Regulation; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D050505:Mutant Proteins / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000201:enzymology; D010012:Osteogenesis; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D053245:RANK Ligand / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D050505:Mutant Proteins; D053245:RANK Ligand; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse