Journal
CELL
Volume 152, Issue 5, Pages 1119-1133Publisher
CELL PRESS
DOI: 10.1016/j.cell.2013.02.002
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Funding
- DFG [SFB 779 TPB8, SFB854 TP7, TP4, TP8, GRK1167, Kr1879/3-1, TPZ]
- DIP grant
- EU FP7 MC-ITN NPlast
- European Regional Development Fund (ERDF)
- Vorhaben: CBBS
- NSFC [31271197]
- Schram Foundation
- European Molecular Biology Organization (EMBO) [EMBO ALTF 884-2011]
- Marie Curie Actions (EMBOCOFUND) [GA-2010-267146]
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The activation of N-methyl-D-aspartate-receptors (NMDARs) in synapses provides plasticity and cell survival signals, whereas NMDARs residing in the neuronal membrane outside synapses trigger neuro-degeneration. At present, it is unclear how these opposing signals are transduced to and discriminated by the nucleus. In this study, we demonstrate that Jacob is a protein messenger that encodes the origin of synaptic versus extrasynaptic NMDAR signals and delivers them to the nucleus. Exclusively synaptic, but not extrasynaptic, NMDAR activation induces phosphorylation of Jacob at serine-180 by ERK1/2. Long-distance trafficking of Jacob from synaptic, but not extrasynaptic, sites depends on ERK activity, and association with fragments of the intermediate filament alpha-internexin hinders dephosphorylation of the Jacob/ERK complex during nuclear transit. In the nucleus, the phosphorylation state of Jacob determines whether it induces cell death or promotes cell survival and enhances synaptic plasticity.
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