Regulation of phosphorylation of tau by cyclin-dependent kinase 5 and glycogen synthase kinase-3 at substrate level.
Microtubule associated protein tau, which is expressed in six alternatively spliced molecular isoforms in human brain, is abnormally hyperphosphorylated in Alzheimer disease and related tauopathies. Here, we show (i) that GSK-3alpha and neither GSK-3beta nor cdk5 can phosphorylate tau at Ser262 and phosphorylation at Ser235 by cdk5 primes phosphorylation at Thr231 by GSK-3alpha/beta; (ii) that tau isoforms with two N-terminal inserts (tau4L, tau3L) are phosphorylated by cdk5 plus GSK-3 at Thr231 markedly more than isoforms lacking these inserts (tau4, tau3); and (iii) that Thr231 is phosphorylated approximately 50% more in free tau than in microtubule-bound tau, and the phosphorylation at this site results in the dissociation of tau from microtubules. These findings suggest that the phosphorylation of tau at Thr231 and Ser262 by cdk5 plus GSK-3, which inhibits its normal biological activity, is regulated both by its amino terminal inserts and its physical state.
Sengupta
Amitabha
A
Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, New York 10314-6399, USA.
Novak
Michal
M
Grundke-Iqbal
Inge
I
Iqbal
Khalid
K
D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008870:Microtubules / Q000378:metabolism; D010766:Phosphorylation; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013379:Substrate Specificity; D016875:tau Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
C054369:MAPT protein, human; D020033:Protein Isoforms; D011994:Recombinant Proteins; D016875:tau Proteins; D051360:Cyclin-Dependent Kinase 5; C495905:CDK5 protein, human; D038362:Glycogen Synthase Kinase 3