Sodium tungstate decreases the phosphorylation of tau through GSK3 inactivation.
Tungstate treatment increases the phosphorylation of glycogen synthase kinase-3beta (GSK3beta) at serine 9, which triggers its inactivation both in cultured neural cells and in vivo. GSK3 phosphorylation is dependent on the activation of extracellular signal-regulated kinases 1/2 (ERK1/2) induced by tungstate. As a consequence of GSK3 inactivation, the phosphorylation of several GSK3-dependent sites of the microtubule-associated protein tau decreases. Tungstate reduces tau phosphorylation only in primed sequences, namely, those prephosphorylated by other kinases before GSK3beta modification, which are serines 198, 199, or 202 and threonine 231. The phosphorylation at these sites is involved in reduction of the interaction of tau with microtubules that occurs in Alzheimer's disease.
Gómez-Ramos
Alberto
A
Centro de Biología Molecular, CSIC/UAM, Facultad de Ciencias, Universidad Autónoma de Madrid, Cantoblanco, Madrid, Spain.
Domínguez
Jorge
J
Zafra
Delia
D
Corominola
Helena
H
Gomis
Ramon
R
Guinovart
Joan J
JJ
Avila
Jesús
J
D000818:Animals; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000187:drug effects*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004793:Enzyme Reactivators / Q000037:antagonists & inhibitors*; D005419:Flavonoids / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology*; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D008094:Lithium / Q000494:pharmacology; D008297:Male; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008958:Models, Molecular; D009447:Neuroblastoma; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D012694:Serine / Q000378:metabolism; D013997:Time Factors; D017973:Tungsten Compounds / Q000494:pharmacology*; D016875:tau Proteins / Q000378:metabolism*
D004791:Enzyme Inhibitors; D004793:Enzyme Reactivators; D005419:Flavonoids; D007328:Insulin; D017973:Tungsten Compounds; D016875:tau Proteins; D012694:Serine; C025399:sodium tungstate(VI); D008094:Lithium; D048052:Mitogen-Activated Protein Kinase 3; D038362:Glycogen Synthase Kinase 3; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one