c-Jun NH2-terminal kinase-interacting protein-3 facilitates phosphorylation and controls localization of amyloid-beta precursor protein.
Abnormal phosphorylation of amyloid-beta precursor protein (APP) is a pathologic feature of Alzheimer's disease. To begin to understand the mechanism of APP phosphorylation, we studied this process in differentiating neurons under normal physiological conditions. We found that c-Jun NH2-terminal kinase (JNK), not cyclin-dependent kinase 5, is required for APP phosphorylation, leading to localized accumulation of phosphorylated APP (pAPP) in neurites. We show that JNK-interacting protein-3 (JIP-3), a JNK scaffolding protein that does not bind APP, selectively increases APP phosphorylation, accumulation of pAPP into processes, and stimulates process extension in both neurons and COS-1 cells. Downregulation of JIP-3 by small interfering RNA impairs neurite extension and reduces the amount of localized pAPP. Finally, whereas stress-activated JNK generates pAPP only in the cell body, concomitant expression of JIP-3 restores pAPP accumulation into neurites. Thus, APP phosphorylation, transport of the generated pAPP into neurites, and neurite extension are interdependent processes regulated by JIP-3/JNK, in a pathway distinct from stress-activated JNK signaling.
Muresan
Zoia
Z
Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-4970, USA.
Muresan
Virgil
V
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D000841:Anisomycin / Q000494:pharmacology; D000873:Anthracenes / Q000494:pharmacology; D015153:Blotting, Western / Q000379:methods; D002460:Cell Line; D002522:Chlorocebus aethiops; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D047468:Immunoprecipitation / Q000379:methods; D051379:Mice; D048057:Mitogen-Activated Protein Kinase 10 / Q000378:metabolism*; D008954:Models, Biological; D016501:Neurites / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D011687:Purines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D000077546:Roscovitine; D014162:Transfection / Q000379:methods
D048868:Adaptor Proteins, Signal Transducing; D016564:Amyloid beta-Protein Precursor; D000873:Anthracenes; D004791:Enzyme Inhibitors; D006131:Growth Inhibitors; D011687:Purines; D034741:RNA, Small Interfering; D000077546:Roscovitine; C432165:pyrazolanthrone; D000841:Anisomycin; D048057:Mitogen-Activated Protein Kinase 10