PP2A-Mediated GSK3 beta Dephosphorylation Is Required for Protocadherin-7-Dependent Regulation of Small GTPase RhoA in Osteoclasts

卷:12

Article

关键词: PROTEIN PHOSPHATASE 2A;    NF-PROTOCADHERIN;    MYELOID-LEUKEMIA;    BONE-RESORPTION;    CELL-ADHESION;    SET;    PHOSPHORYLATION;    DIFFERENTIATION;    TARGET;    RANKL;   

DOI  :  10.3390/cells12151967

来源: SCIE

【 摘 要 】

Protocadherin-7 (Pcdh7) is a member of the non-clustered protocadherin delta 1 subgroup of the 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, the mechanisms by which small GTPases are regulated downstream of Pcdh7 remain unclear. Here, we demonstrate that protein phosphatase 2A (PP2A)-mediated dephosphorylation of Glycogen synthase kinase-3 beta (GSK3 beta) is required for Pcdh7-dependent activation of RhoA during osteoclast differentiation. Pcdh7-deficient (Pcdh7-/-) cells showed impaired PP2A activity, despite their normal expression of PP2A. GSK3 beta, whose activity is regulated by its inhibitory phosphorylation at Ser9, was dephosphorylated during osteoclast differentiation in a Pcdh7-dependent manner. Inhibition of protein phosphatase by okadaic acid reduced dephosphorylation of GSK3 beta in Pcdh7(+/+) cells, while activation of PP2A by DT 061 rescued impaired dephosphorylation of GSK3 beta in Pcdh7(-/-) cells. Inhibition of GSK3 beta by AR A014418 inhibited RANKL-induced RhoA activation and osteoclast differentiation in Pcdh7(+/+) cells. On the other hand, DT-061 treatment rescued impaired RhoA activation and RANKL-induced osteoclast differentiation in Pcdh7(-/-) cells. Taken together, these results demonstrate that PP2A dephosphorylates GSK3 beta and thereby activates it in a Pcdh7-dependent manner, which is required for activation of small GTPase RhoA and proper osteoclast differentiation.