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

Zoia Muresan, Virgil Muresan

Research output: Contribution to journalArticlepeer-review

68 Scopus citations

Abstract

Abnormal phosphorylation of amyloid-β 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.

Original languageEnglish (US)
Pages (from-to)3741-3751
Number of pages11
JournalJournal of Neuroscience
Volume25
Issue number15
DOIs
StatePublished - Apr 13 2005
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Keywords

  • Alzheimer's disease
  • Amyloid-β precursor protein
  • Axonal transport
  • JNK-interacting protein
  • Kinesin
  • c-Jun NH-terminal kinase

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