Phosphorylation of microtubule-associated protein tau by stress-activated protein kinases in intact cells

Abstract

Tau is a microtubule-associated protein that is abnormally hyperphosphorylated in the filamentous lesions that define a number of neurodegenerative diseases collectively referred to as tauopathies. We previously showed that stress-activated protein (SAP) kinases phosphorylate tau protein at many of the hyperphosphorylated sites in vitro. Here we have developed a system to study the effects of five SAP kinases (SAPK1c/JNK1, SAPK2a/p38α, SAPK2b/p38β, SAPK3/p38γ and SAPK4/p38δ) on tau phosphorylation in intact cells. All kinases phosphorylated tau, albeit at different efficiencies. Tau was a good substrate for SAPK3/p38γ and SAPK4/p38δ, a reasonable substrate for SAPK2b/p38β and a relatively poor substrate for SAPK2a/p38α and SAPK1c/JNK1. These findings indicate that the aberrant activation of SAP kinases, especially SAPK3/p38γ and SAPK4/p38δ, could play an important role in the abnormal hyperphosphorylation of tau that is an invariant feature of the tauopathies.