Modulation of tau phosphorylation within its microtubule-binding domain by cellular thiols.
Tau is a microtubule-stabilizing protein that is functionally modulated by alterations in its phosphorylation state. Because phosphorylation regulates both normal and pathological tau functioning, it is of importance to identify the signaling pathways that regulate tau phosphorylation in vivo. The present study examined changes in tau phosphorylation and function in response to modulation of cellular thiol content. Treatment of cells with phenylarsine oxide, which reacts with vicinal thiols, selectively increased tau phosphorylation within its microtubule-binding domain, at the non-Ser/Thr-Pro sites Ser262/356, while decreasing tau phosphorylation at Ser/ Thr-Pro sites outside this region. This increase in tau phosphorylation correlated with a decrease in the amount of tau associated with the cytoskeleton and decreased microtubule stability. Phenylarsine oxide-induced tau phosphorylation was inhibited by oxidants and by the protein kinase inhibitor staurosporine. Although staurosporine completely eliminated the increase in tau phosphorylation at Ser262/356, as detected by immunostaining with 12E8, it had a comparatively minor effect on the changes in tau localization induced by phenylarsine oxide. The results suggest that regulation of cellular thiols is important for modulating tau phosphorylation and function in situ. Additionally, although phosphorylation of Ser262/356 decreases tau's interaction with the cytoskeleton, phosphorylation of these residues alone is not sufficient for the phenylarsine oxide-induced changes in tau localization.
Jenkins
S M
SM
Department of Psychiatry, University of Alabama at Birmingham, 35294-0017, USA.
Johnson
G V
GV
D000818:Animals; D001152:Arsenicals / Q000494:pharmacology; D001665:Binding Sites; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000648:ultrastructure; D003599:Cytoskeleton / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008870:Microtubules / Q000378:metabolism*; D009447:Neuroblastoma; D016877:Oxidants / Q000494:pharmacology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D019311:Staurosporine / Q000494:pharmacology; D013438:Sulfhydryl Compounds / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D016875:tau Proteins / Q000737:chemistry / Q000378:metabolism*
D001152:Arsenicals; D004791:Enzyme Inhibitors; D016877:Oxidants; D047428:Protein Kinase Inhibitors; D013438:Sulfhydryl Compounds; D016875:tau Proteins; C029341:oxophenylarsine; D019311:Staurosporine