Role of tau phosphorylation by glycogen synthase kinase-3beta in the regulation of organelle transport.
Anterograde organelle transport is known to be inhibited by overexpression of the microtubule-associated protein tau in cultured cells. However, the molecular mechanism regulating this function of tau protein has not previously been understood. We found that in PC12 cells treated with NGF or fibroblast growth factor-2, glycogen synthase kinase-3beta and tau were upregulated simultaneously from around day 2 of differentiation, with increasing glycogen synthase kinase-3-mediated tau phosphorylation. This phosphorylation did not alter tau's ability to bind to microtubules but appeared to be required for the maintenance of the anterograde organelle transport in differentiated cells. Lithium, alsterpaullone or valproate, three independent glycogen synthase kinase-3 inhibitors, but not butyrolactone 1, an inhibitor of cyclin-dependent protein kinases, induced mitochondrial clustering in association with tau dephosphorylation. In CHO cells transfected with human tau(441), mitochondrial clustering was found in cells in which tau was unphosphorylated. These findings raise the possibility that the phosphorylation of tau by glycogen synthase kinase-3 might be involved in the regulation of organelle transport.
Tatebayashi
Yoshitaka
Y
New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, New York, NY 10314, USA.
Haque
Niloufar
N
Tung
Yunn-Chyn
YC
Iqbal
Khalid
K
Grundke-Iqbal
Inge
I
D000818:Animals; D001692:Biological Transport; D016466:CHO Cells; D002454:Cell Differentiation / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D008094:Lithium / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D020932:Nerve Growth Factor / Q000494:pharmacology; D016501:Neurites / Q000187:drug effects; D015388:Organelles / Q000378:metabolism*; D016716:PC12 Cells; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects; D014162:Transfection; D015854:Up-Regulation / Q000187:drug effects; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
D016875:tau Proteins; D016222:Fibroblast Growth Factor 2; D020932:Nerve Growth Factor; D008094:Lithium; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3