Rapid Alzheimer-like phosphorylation of tau by the synergistic actions of non-proline-dependent protein kinases and GSK-3.
Tau protein from Alzheimer disease (AD) brain is phosphorylated at eleven Ser/Thr-Pro and nine Ser/Thr-X sites. The former sites are phosphorylated by proline-dependent protein kinases (PDPKs), the latter by non-PDPKs. The identities of both the PDPKs and non-PDPKs involved in AD tau hyperphosphorylation are still to be established. In this study we have analyzed the interactions between a PDPK (GSK-3) and several non-PDPKs (A-kinase, C-kinase, CK-1, CaM kinase II) in the phosphorylation of one isoform (tau 39) of human tau. We found that the rate of phosphorylation of tau 39 by GSK-3 was increased several-fold if tau were first prephosphorylated by the non-PDPKs. Further, several Alzheimer-like epitopes in tau can be induced only slowly after phosphorylation of tau by GSK-3 alone. After a prephosphorylation of tau by the non-PDPKs, however, the rate of induction of these epitopes by GSK-3 is increased several-fold. These results suggest that one role of non-PDPK-catalyzed phosphorylation is the modulation of PDPK-catalyzed phosphorylation of tau in AD brain.
Singh
T J
TJ
New York State Institute for Basic Research in Developmental Disabilities, Staten Island 10314.
Haque
N
N
Grundke-Iqbal
I
I
Iqbal
K
K
D000544:Alzheimer Disease / Q000378:metabolism*; D000906:Antibodies / Q000276:immunology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D000939:Epitopes / Q000276:immunology; D038362:Glycogen Synthase Kinase 3; D006801:Humans; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D016875:tau Proteins / Q000276:immunology / Q000378:metabolism*
D000906:Antibodies; D000939:Epitopes; D016875:tau Proteins; D011494:Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3