NUCLEAR EXPORT OF THE STRESS-ACTIVATED PROTEIN-KINASE P38 MEDIATED BYITS SUBSTRATE MAPKAP KINASE-2

Background: Mitogen-activated protein (MAP) kinases (or extracellular signal regulated kinases; Erks) and stress-activated protein (SAP) kin ases mediate cellular responses to a wide variety of signals. in the E rk MAP kinase pathway, activation of MAP kinases takes place in the cy toplasm and the activated enzyme moves to the nucleus. This translocat ion to the nucleus is essential to MAP kinase signalling because it en ables the kinase to phosphorylate transcription factors. Whether compo nents of the pathway mediated by the SAP kinase p38 change their cellu lar location on activation is not clear; we have therefore studied the cellular localisation of components of this pathway before and after stimulation. Results: The p38 SAP kinase substrate MAP-kinase-activate d protein kinase-2 (MAPKAP kinase-2) contains a putative nuclear local isation signal which we show is functional and required for activation by a variety oi stimuli, Following phosphorylation of MAPKAP kinase-e , nuclear p38 was exported to the cytoplasm in a complex with MAPKAP k inase-2, Export of MAPKAP kinase-2 required phosphorylation by p38 but did not appear to require the kinase activity of MAPKAP kinase-2, The p38 activators MKK3 and MKK6 were present in both the nucleus and the cytoplasm, consistent with a role in activating p38 in the nucleus. C onclusions: In the p38 SAP kinase pathway, MAPKAP kinase-e serves both as an effector of p38 by phosphorylating substrates and as a determin ant of cellular localisation of p38. Nuclear export of p38 and MAPKAP kinase-e may permit them to phosphorylate substrates in the cytoplasm.