[摘要]：GSK-3 beta (glycogen synthase kinase-3 beta), a crucial tau kinase, negatively regulates PP2A (protein phosphatase 2A), the most active tau phosphatase that is suppressed in the brain in AD (Alzheimer's disease). However, the molecular mechanism is not understood. In the present study we found that activation of GSK-3 beta stimulates the inhibitory phosphorylation of PP2A at Tyr(307) (pY307-PP2A), whereas inhibition of GSK-3 beta decreased the level of pY307-PP2A both in vitro and in vivo. GSK-3 beta is a serine/threonine kinase that can not phosphorylate tyrosine directly, therefore we measured PTP1B (protein tyrosine phosphatase 1B) and Src (a tyrosine kinase) activities. We found that GSK-3 beta can modulate both PTP1B and Src protein levels, but it only inhibits PTP1B activity, with no effect on Src. Furthermore, only knockdown of PTP1B but not Src by siRNA (small interfering RNA) eliminates the effects of GSK-3 beta on PP2A. GSK-3 beta phosphorylates PTP1B at serine residues, and activation of GSK-3 beta reduces the mRNA level of PTP1B. Additionally, we also observed that GSK-3 negatively regulates the protein and mRNA levels of PP2A, and knockdown of CREB (cAMP-response-element-binding protein) abolishes the increase in PP2A induced by GSK-3 inhibition. The results of the present study suggest that GSK-3 beta inhibits PP2A by increasing the 'inhibitory Tyr(307) phosphorylation and decreasing the expression of PP2A, and the mechanism involves inhibition of PTP1B and CREB.
