Phosphorylation of human tau protein by microtubule-associated kinases: GSK3beta and cdk5 are key participants.
Microtubules (MTs), primarily composed of alpha and beta tubulin polymers, must often work in concert with microtubule-associated proteins (MAPs) in order to modulate their functional demands. In a mature brain neuron, one of the key MAPs that resides primarily in the axonal compartment is the tau protein. Tau, in the adult human brain, is a set of six protein isoforms, whose binding affinity to MTs can be modulated by phosphorylation. In addition to the role that phosphorylation of tau plays in the "normal" physiology of neurons, hyperphosphorylated tau is the primary component of the fibrillary pathology in Alzheimer's disease (AD). Although many protein kinases are known to phosphorylate tau in vitro, the in vivo players contributing to the hyperphosphorylation of tau remain elusive. The experiments in this study attempt to define which protein kinases and protein phosphatases reside in the associated network of microtubules, thereby being strategically positioned to influence the phosphorylation of tau. Microtubule fractions are utilized to determine which of the microtubule-associated kinases most readily impacts the phosphorylation of tau at "AD-like" sites. Results from this study indicate that PKA, CK1, GSK3beta, and cdk5 associate with microtubules. Among the MT-associated kinases, GSK3beta and cdk5 most readily contribute to the ATP-induced "AD-like" phosphorylation of tau.
Flaherty
D B
DB
Department of Cell Biology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Soria
J P
JP
Tomasiewicz
H G
HG
Wood
J G
JG
D000255:Adenosine Triphosphate / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D047388:Casein Kinases; D002417:Cattle; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism / Q000494:pharmacology; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3; D006801:Humans; D015151:Immunoblotting; D007701:Kinetin; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008870:Microtubules / Q000737:chemistry / Q000201:enzymology; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D013347:Subcellular Fractions / Q000737:chemistry / Q000201:enzymology; D016875:tau Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*
D004791:Enzyme Inhibitors; D008869:Microtubule-Associated Proteins; D011687:Purines; D016875:tau Proteins; C090046:olomoucine; D000255:Adenosine Triphosphate; D011494:Protein Kinases; D047388:Casein Kinases; D051360:Cyclin-Dependent Kinase 5; D017868:Cyclic AMP-Dependent Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C495905:CDK5 protein, human; D018844:Cyclin-Dependent Kinases; D038362:Glycogen Synthase Kinase 3; D007701:Kinetin