title: Glycogen synthase kinase-3β regulates Tyr307 phosphorylation of protein phosphatase-2A via protein tyrosine phosphatase 1B but not Src.
abstract: GSK-3β (glycogen synthase kinase-3β), 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-3β stimulates the inhibitory phosphorylation of PP2A at Tyr307 (pY307-PP2A), whereas inhibition of GSK-3β decreased the level of pY307-PP2A both in vitro and in vivo. GSK-3β 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-3β 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-3β on PP2A. GSK-3β phosphorylates PTP1B at serine residues, and activation of GSK-3β 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-3β inhibits PP2A by increasing the inhibitory Tyr307 phosphorylation and decreasing the expression of PP2A, and the mechanism involves inhibition of PTP1B and CREB.
authors.affiliation: Department of Pathophysiology, Key Laboratory of Neurological Diseases of Chinese Ministry of Education, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P R China.
authors.forename: Xiu-Qing
authors.initials: XQ
authors.lastname: Yao
authors.forename: Xiao-Xue
authors.initials: XX
authors.lastname: Zhang
authors.forename: Yang-Yang
authors.initials: YY
authors.lastname: Yin
authors.forename: Bin
authors.initials: B
authors.lastname: Liu
authors.forename: Dan-Ju
authors.initials: DJ
authors.lastname: Luo
authors.forename: Dan
authors.initials: D
authors.lastname: Liu
authors.forename: Ning-Ning
authors.initials: NN
authors.lastname: Chen
authors.forename: Zhong-Fei
authors.initials: ZF
authors.lastname: Ni
authors.forename: Xiong
authors.initials: X
authors.lastname: Wang
authors.forename: Qun
authors.initials: Q
authors.lastname: Wang
authors.forename: Jian-Zhi
authors.initials: JZ
authors.lastname: Wang
authors.forename: Gong-Ping
authors.initials: GP
authors.lastname: Liu
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D057809:HEK293 Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D012694:Serine / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014443:Tyrosine / Q000378:metabolism; D000077191:Wortmannin; D019061:src-Family Kinases / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism
chemical_list: D000730:Androstadienes; D017362:Cyclic AMP Response Element-Binding Protein; D007211:Indoles; D008301:Maleimides; D012333:RNA, Messenger; C417521:SB 216763; D016875:tau Proteins; D014443:Tyrosine; D012694:Serine; D019061:src-Family Kinases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D054648:Protein Phosphatase 2; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D000077191:Wortmannin