AMINO-TERMINAL REGION OF THE BETA-AMYLOID PRECURSOR PROTEIN ACTIVATESMITOGEN-ACTIVATED PROTEIN-KINASE

The secreted form of the beta-amyloid precursor protein (beta-APP) has previously been shown to stimulate mitogen-activated protein (MAP) ki nases in PC-12 pheochromocytoma cells. The amino-terminal half of secr eted beta-APP contains a region rich in cysteine residues reminiscent of cysteine-rich binding regions in other families of extracellular pr oteins. We found that reductive alkylation of disulfide linkages elimi nated the ability of secreted beta-APP to activate MAP kinase. To conf irm the role of the cysteine-rich aminoterminal region, fragments repr esenting the amino- and carboxyl-terminal halves of secreted beta-APP were expressed in bacteria as fusion proteins and purified. Ten-minute treatment with the amino-terminal segment of beta-APP activated MAP k inase approximately 15-fold, while the carboxyl segment had no effect, The amino-terminal fragment, like intact secreted beta-APP, was subst antially inactivated by reduction of sulfhydryl groups. These results suggest that the amino-terminal region of beta-APP is responsible for activation of MAP kinase and that it requires structural loops created by disulfide linkages for activity.