Potentiation of GSK-3-catalyzed Alzheimer-like phosphorylation of human tau by cdk5.
Tau protein from Alzheimer disease (AD) brain is hyperphosphorylated by both proline-dependent protein kinases (PDPKs) and non-PDPKs. It is presently unclear how PDPKs and non-PDPKs interact in tau hyperphosphorylation. Previously we have shown that non-PDPKs can positively modulate the activity of a PDPK (GSK-3) in tau phosphorylation (Singh et al. (1995) FEBS Lett. 358, 267-272). In this study we have investigated whether (A) non-PDPKs can also modulate the activity of the PDPK, cdk5, (B) a PDPK can modulate the activities of another PDPK, as well as non-PDPKs. We found that, like GSK-3, the activity of cdk5 is stimulated if tau were first prephosphorylated by any of several non-PDPKs (A-kinase, C-kinase, CK-1, CaM-kinase II). Prephosphorylation of tau by cdk5 stimulated both the rate and extent of a subsequent phosphorylation catalyzed by GSK-3. Under these conditions thr 231 phosphorylation was especially enhanced (9-fold). No significant stimulation of phosphorylation was observed when the order of these kinases was reversed (i.e. GSK-3 followed by cdk5). By contrast, prephosphorylation of tau by cdk5 served to inhibit subsequent phosphorylation catalyzed by C-kinase and CK-1, but not by A-kinase or CaM-kinase II. Our results suggest that in tau hyperphosphorylation in AD brain, cdk5-catalyzed phosphorylation may serve to upregulate the activity of GSK-3 and down-regulate the activities of C-kinase and CK-1.
Sengupta
A
A
New York State Institute for Basic Research in Developmental Disabilities, Staten Island 10314, USA.
Wu
Q
Q
Grundke-Iqbal
I
I
Iqbal
K
K
Singh
T J
TJ
D000544:Alzheimer Disease / Q000378:metabolism*; D000906:Antibodies / Q000378:metabolism; D001665:Binding Sites; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D047388:Casein Kinases; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases; D000939:Epitopes; D038362:Glycogen Synthase Kinase 3; D006801:Humans; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D016875:tau Proteins / Q000276:immunology / Q000378:metabolism*
D000906:Antibodies; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D047388:Casein Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases; D000939:Epitopes; D038362:Glycogen Synthase Kinase 3; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D016875:tau Proteins; C495905:CDK5 protein, human