PTEN regulation by the Akt/GSK-3β axis during RANKL signaling

Hyun Duk Jang, Ji Yeon Noh, Ji Hye Shin, Jing Jing Lin, Soo Young Lee

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46 Scopus citations


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.

Original languageEnglish
Pages (from-to)126-131
Number of pages6
Issue number1
StatePublished - Jul 2013

Bibliographical note

Funding Information:
We thank T. Kitamura for providing PLAT-E cells and pMX vectors. This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean Government (MEST; R0A-2008-000-20001-0 ; R31-2008-000-10010-0 ; No. 2012–0000952 ; No. 2012M3A9C5048708 ). H. Jang was supported by the RP-Grant 2010 of Ewha Womans University . J.S., and J.L. were supported by the second stage of the Brain Korea 21 Project .


  • Akt
  • GSK-3β
  • Osteoclastogenesis
  • PTEN


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