Mitogen activated protein (MAP) kinase transforms tau protein into an Alzheimer-like state.
The microtubule-associated protein tau is a major component of the paired helical filaments (PHFs) observed in Alzheimer's disease brains. The pathological tau is distinguished from normal tau by its state of phosphorylation, higher apparent M(r) and reaction with certain antibodies. However, the protein kinase(s) have not been characterized so far. Here we describe a protein kinase from brain which specifically induces the Alzheimer-like state in tau protein. The 42 kDa protein belongs to the family of mitogen activated protein kinases (MAPKs) and is activated by tyrosine phosphorylation. It is capable of phosphorylating Ser-Pro and Thr-Pro motifs in tau protein (approximately 14-16 P1 per tau molecule). By contrast, other proline directed Ser/Thr kinases such as p34(cdc2) combined with cyclin A or B have only minor effects on tau phosphorylation. We propose that MAP kinase is abnormally active in Alzheimer brain tissue, or that the corresponding phosphatases are abnormally passive, due to a breakdown of the normal regulatory mechanisms.
Drewes
G
G
Max-Planck-Unit for Structural Molecular Biology, Hamburg, Germany.
Lichtenberg-Kraag
B
B
Döring
F
F
Mandelkow
E M
EM
Biernat
J
J
Goris
J
J
Dorée
M
M
Mandelkow
E
E
D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000201:enzymology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002417:Cattle; D002852:Chromatography, Ion Exchange; D003001:Cloning, Molecular; D004591:Electrophoresis, Polyacrylamide Gel; D004789:Enzyme Activation; D006801:Humans; D008970:Molecular Weight; D010766:Phosphorylation; D019000:Phosphotyrosine; D011494:Protein Kinases / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D011994:Recombinant Proteins / Q000302:isolation & purification / Q000378:metabolism; D012016:Reference Values; D013379:Substrate Specificity; D013552:Swine; D014443:Tyrosine / Q000031:analogs & derivatives / Q000032:analysis; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
D011994:Recombinant Proteins; D016875:tau Proteins; D019000:Phosphotyrosine; D014443:Tyrosine; D011494:Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases