Hyperphosphorylation of the cytoskeletal protein Tau by the MAP-kinase PK40erk2: regulation by prior phosphorylation with cAMP-dependent protein kinase A.
PK40erk2 is a MAP kinase which phosphorylates recombinant hTau40 up to 14 moles of phosphate/mole, markedly slowing its electrophoretic mobility. PK40erk2 acting on TAU is expected to cause the appearance of Alzheimer's disease-specific phosphoepitopes, detectable by specific antibodies. Maximal phosphorylation in vitro of hTau40 by PKAcat incorporates only 2-3 moles of phosphate/mole. Consequent, but smaller, reduction in electrophoretic mobility is seen, but not the formation of Alzheimer-specific or hyperphosphorylation-specific epitopes. Phosphorylation of hTau40 by PKAcat sharply reduces the number of phosphates that can now be introduced by PK40erk2 to 5-6 moles/mole, instead of the expected 11 moles/mole. Thus, prior phosphorylation by PKA, a non-proline-directed protein kinase, regulates the conformation of the protein substrate Tau so as to make some sites very much less accessible to phosphorylation by the proline-directed kinase, PK40erk2.
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000201:enzymology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002417:Cattle; D003001:Cloning, Molecular; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D015180:Electrophoresis, Gel, Two-Dimensional; D004591:Electrophoresis, Polyacrylamide Gel; D004926:Escherichia coli; D006706:Homeostasis; D007700:Kinetics; D046911:Macromolecular Substances; D019950:Mitogen-Activated Protein Kinase 1; D010449:Peptide Mapping; D010748:Phosphopeptides / Q000737:chemistry / Q000302:isolation & purification; D010761:Phosphorus Radioisotopes; D010766:Phosphorylation; D011994:Recombinant Proteins / Q000378:metabolism; D013997:Time Factors; D016875:tau Proteins / Q000378:metabolism*
D046911:Macromolecular Substances; D010748:Phosphopeptides; D010761:Phosphorus Radioisotopes; D011994:Recombinant Proteins; D016875:tau Proteins; D000255:Adenosine Triphosphate; D017868:Cyclic AMP-Dependent Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1