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PMID: 15829626 Published · ppublish English Comparative Study Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

c-Jun NH2-terminal kinase-interacting protein-3 facilitates phosphorylation and controls localization of amyloid-beta precursor protein.

The Journal of neuroscience : the official journal of the Society for Neuroscience ·Vol. 25 ·No. 15 ·2005-04-13 ·Pages 3741-51

Muresan Z, Muresan V

Abstract

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.

MeSH Terms
Adaptor Proteins, Signal Transducing/metabolism Amyloid beta-Protein Precursor/metabolism Animals Anisomycin/pharmacology Anthracenes/pharmacology Blotting, Western/methods Cell Line Chlorocebus aethiops Enzyme Inhibitors/pharmacology Gene Expression Regulation/drug effects,physiology Growth Inhibitors/pharmacology Humans Immunohistochemistry/methods Immunoprecipitation/methods Mice Mitogen-Activated Protein Kinase 10/metabolism Models, Biological Neurites/drug effects,metabolism Neurons/cytology,drug effects,metabolism Phosphorylation/drug effects Protein Binding/drug effects Purines/pharmacology RNA, Small Interfering/pharmacology Roscovitine Transfection/methods
Chemicals
Adaptor Proteins, Signal Transducing Amyloid beta-Protein Precursor Anthracenes Enzyme Inhibitors Growth Inhibitors Purines RNA, Small Interfering Roscovitine pyrazolanthrone Anisomycin Mitogen-Activated Protein Kinase 10
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Muresan Zoia
Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-4970, USA.
Muresan Virgil
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Article Info
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Abbr.
J Neurosci
ISSN
1529-2401
DOI
10.1523/JNEUROSCI.0152-05.2005
Published
2005-04-13
Pages
3741-51
Language
English
Region
United States
NLM ID
8102140
PMCID
PMC6724916
Subset
IM
Grants
NIA NIH HHS · P50 AG008012 · United States
NIGMS NIH HHS · R01 GM068596 · United States
NIGMS NIH HHS · 1R01GM068596-01A1 · United States
NIA NIH HHS · AG08012 · United States
External Links
PubMed source DOI: 10.1523/JNEUROSCI.0152-05.2005 PMC Full Text View journal details
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