Hyperphosphorylation of human TAU by brain kinase PK40erk beyond phosphorylation by cAMP-dependent PKA: relation to Alzheimer's disease.

Abnormal hyperphosphorylation of the cytoskeletal protein TAU is seen in the characteristic paired helical filaments [neurofibrillary tangles] of Alzheimer's disease [AD]. A recently described protein kinase, PK40erk, (1) a member of the ERK family of kinases, can produce in vitro many of the properties of Alzheimer-like hyperphosphorylated TAU. cAMP-dependent protein kinase A [PKA] phosphorylates TAU to a lesser extent; however, the product is not like the hyperphosphorylated TAU of AD in several important respects. We now report that in vitro PK40erk, a candidate for the enzyme responsible for TAU hyperphosphorylation in AD, will further phosphorylate TAU that was previously saturated by protein kinase A, provided that the concentrations of free uncomplexed ATP are low. Interestingly, the actions of different kinases on TAU are not independent, but may depend on the order in which they work on TAU; i.e., prior phosphorylation by PKA partially inhibits the action of PK40erk.