Regulated secretion of amyloid precursor protein by TrkA receptor stimulation in rat pheochromocytoma-12 cells is mitogen activated protein kinase sensitive

We have shown recently in the pheochromocytoma PC-12 cell line, that the ac tivation of the high-affinity receptor for nerve growth factor (NGF), tyros ine kinase receptor (TrkA), results in increased secretion of the amyloid p recursor protein (APP) into the culture medium. In order to reveal through which TrkA-associated signaling pathway the secretory APP processing is med iated, signaling cascades activated by TrkA stimulation were selectively in hibited under conditio ns of selective TrkA stimulation via non-NGF mechani sms and APP secretion into the culture medium was followed by Western analy sis. Our data demonstrate, that activation of mitogen activated protein (MA P) kinase alone is sufficient to promote APP secretion, whereas inhibition of MAP kinase will reduce APP secretion only when phospholipase C gamma or phosphatidylinositol 3-kinase are additionally inhibited. This suggests tha t pharmacological manipulations activating the MAP kinase pathway may resul t in increased secretory APP processing. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.