Signalling through NMDA receptors (NMDARs) can trigger cell death or survival depending on whether activation of such receptors occurs at extrasynaptic or synaptic sites, respectively. It is unclear how these opposing signals are communicated to and discriminated by the nucleus, but the authors of this study show that differential phosphorylation of JACOB relays the origin of the NMDAR signal to the nucleus. Synaptic NMDAR activation induces phosphorylation of JACOB at Ser180 by ERK1/2 (extracellular receptor-activated MAP kinase 1 and 2) and ERK1/2-dependent nuclear translocation. During nuclear transit, phosphorylated JACOB associates with the intermediate filament protein α-internexin, which hinders dephosphorylation. Once in the nucleus, phosphorylated JACOB inactivates the transcription factor cyclic AMP-responsive element-binding protein (CREB) to promote cell survival and enhance synaptic plasticity.