Hyperphosphorylation of the Cytoskeletal Protein Tau by the MAP-Kinase PK40 erk2: Regulation by Prior Phosphorylation with cAMP-Dependent Protein Kinase A

Abstract

PK40 erk2 is a MAP kinase which phosphorylates recombinant hTau40 up to 14 moles of phosphate/mole, markedly slowing its electrophoretic mobility. PK40 erk2 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 PKA cat 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 PKA cat sharply reduces the number of phosphates that can now be introduced by PK40 erk2 to 5-6 moles/mole, instead of the expected 11 moles/mole. Thus, prior phosphorylation by PKA, a nonproline-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, PK40 erk2.