Phosphorylation of thr(668) in the cytoplasmic domain of the Alzheimer's disease amyloid precursor protein by stress-activated protein kinase 1b (JunN-terminal kinase-3)

Threonine(668) (thr(668)) within the carboxy-terminus of the Alzheimer's di sease amyloid precursor protein (APP) is a known in vivo phosphorylation si te. Phosphorylation of APPthr(668) is believed to regulate APP function and metabolism. Thr(668) precedes a proline, which suggests that it is targete d for phosphorylation by proline-directed kinase(s). We have investigated t he ability of four major neuronally active proline-directed kinases, cyclin dependent protein kinase-5, glycogen synthase kinase-3 beta, p42 mitogen-a ctivated protein kinase and stress-activated protein kinase-lb, to phosphor ylate Appthr(668) and report here that SAPK1b induces robust phosphorylatio n of this site both in vitro and in vivo. This finding provides a molecular framework to link cellular stresses with APP metabolism in both normal and disease states.