PP2A-Mediated GSK3β Dephosphorylation Is Required for Protocadherin-7-Dependent Regulation of Small GTPase RhoA in Osteoclasts

Protocadherin-7 (Pcdh7) is a member of the non-clustered protocadherin δ1 subgroup cadherin superfamily. Pcdh7 has been revealed to control osteoclast differentiation by regulating Rho-family small GTPases, RhoA and Rac1, through its intracellular SET binding domain. However, mechanisms which GTPases are regulated downstream remain unclear. Here, we demonstrate that protein phosphatase 2A (PP2A)-mediated dephosphorylation Glycogen synthase kinase-3β (GSK3β) required for Pcdh7-dependent activation during differentiation. Pcdh7-deficient (Pcdh7−/−) cells showed impaired PP2A activity, despite their normal expression PP2A. GSK3β, whose activity inhibitory phosphorylation at Ser9, was dephosphorylated in manner. Inhibition okadaic acid reduced GSK3β Pcdh7+/+ cells, while DT−061 rescued Pcdh7−/− cells. AR−A014418 inhibited RANKL-induced On other hand, DT-061 treatment Taken together, these results dephosphorylates thereby activates it manner, GTPase proper