title: Both binding and activation of p38 mitogen-activated protein kinase (MAPK) play essential roles in regulation of the nucleocytoplasmic distribution of MAPK-activated protein kinase 5 by cellular stress.
abstract: The p38 mitogen-activated protein kinase (MAPK) pathway is an important mediator of cellular responses to environmental stress. Targets of p38 include transcription factors, components of the translational machinery, and downstream serine/threonine kinases, including MAPK-activated protein kinase 5 (MK5). Here we have used enhanced green fluorescent protein fusion proteins to analyze the subcellular localization of MK5. Although this protein is predominantly nuclear in unstimulated cells, MK5 shuttles between the nucleus and the cytoplasm. Furthermore, we have shown that the C-terminal domain of MK5 contains both a functional nuclear localization signal (NLS) and a leucine-rich nuclear export signal (NES), indicating that the subcellular distribution of this kinase reflects the relative activities of these two signals. In support of this, we have shown that stress-induced activation of the p38 MAPK stimulates the chromosomal region maintenance 1 protein-dependent nuclear export of MK5. This is regulated by both binding of p38 MAPK to MK5, which masks the functional NLS, and stress-induced phosphorylation of MK5 by p38 MAPK, which either activates or unmasks the NES. These properties may define the ability of MK5 to differentially phosphorylate both nuclear and cytoplasmic targets or alternatively reflect a mechanism whereby signals initiated by activation of MK5 in the nucleus may be transmitted to the cytoplasm.
authors.affiliation: Department of Biochemistry. Department of Pharmacology, Institute of Medical Biology, University of Tromsø, N-9037 Tromsø, Norway. olems@fagmed.uit.no
authors.forename: Ole Morten
authors.initials: OM
authors.lastname: Seternes
authors.forename: Bjarne
authors.initials: B
authors.lastname: Johansen
authors.forename: Beate
authors.initials: B
authors.lastname: Hegge
authors.forename: Mona
authors.initials: M
authors.lastname: Johannessen
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Keyse
authors.forename: Ugo
authors.initials: U
authors.lastname: Moens
mesh_terms: D016475:3T3 Cells; D021581:Active Transport, Cell Nucleus; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D002522:Chlorocebus aethiops; D003600:Cytosol / Q000378:metabolism; D004789:Enzyme Activation; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D005807:Genes, Overlapping; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D028884:Karyopherins / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008969:Molecular Sequence Data; D019913:Nuclear Localization Signals / Q000502:physiology; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases; D000097606:Exportin 1 Protein
chemical_list: D005231:Fatty Acids, Unsaturated; D047908:Intracellular Signaling Peptides and Proteins; D028884:Karyopherins; D020928:Mitogen-Activated Protein Kinases; D019913:Nuclear Localization Signals; D017346:Protein Serine-Threonine Kinases; D018160:Receptors, Cytoplasmic and Nuclear; D011993:Recombinant Fusion Proteins; D048051:p38 Mitogen-Activated Protein Kinases; D000097606:Exportin 1 Protein; C111049:MAP-kinase-activated kinase 5; C038753:leptomycin B