PMID:15577943

Citation	Seternes, OM, Mikalsen, T, Johansen, B, Michaelsen, E, Armstrong, CG, Morrice, NA, Turgeon, B, Meloche, S, Moens, U and Keyse, SM (2004) Activation of MK5/PRAK by the atypical MAP kinase ERK3 defines a novel signal transduction pathway. EMBO J. 23:4780-91
Abstract	Extracellular signal-regulated kinase 3 (ERK3) is an atypical mitogen-activated protein kinase (MAPK), which is regulated by protein stability. However, its function is unknown and no physiological substrates for ERK3 have yet been identified. Here we demonstrate a specific interaction between ERK3 and MAPK-activated protein kinase-5 (MK5). Binding results in nuclear exclusion of both ERK3 and MK5 and is accompanied by ERK3-dependent phosphorylation and activation of MK5 in vitro and in vivo. Endogenous MK5 activity is significantly reduced by siRNA-mediated knockdown of ERK3 and also in fibroblasts derived from ERK3-/- mice. Furthermore, increased levels of ERK3 protein detected during nerve growth factor-induced differentiation of PC12 cells are accompanied by an increase in MK5 activity. Conversely, MK5 depletion causes a dramatic reduction in endogenous ERK3 levels. Our data identify the first physiological protein substrate for ERK3 and suggest a functional link between these kinases in which MK5 is a downstream target of ERK3, while MK5 acts as a chaperone for ERK3. Our findings provide valuable tools to further dissect the regulation and biological roles of both ERK3 and MK5.
Links	PubMed PMC535098 Online version:10.1038/sj.emboj.7600489
Keywords	Active Transport, Cell Nucleus/physiology; Animals; COS Cells; Cell Nucleus/metabolism; Cercopithecus aethiops; Cytoplasm/metabolism; Enzyme Activation; Humans; Intracellular Signaling Peptides and Proteins; Mice; Mice, Knockout; Mitogen-Activated Protein Kinase 6/genetics; Mitogen-Activated Protein Kinase 6/metabolism; Protein Binding; Protein-Serine-Threonine Kinases/genetics; Protein-Serine-Threonine Kinases/metabolism; RNA, Small Interfering/genetics; RNA, Small Interfering/metabolism; Recombinant Fusion Proteins/genetics; Recombinant Fusion Proteins/metabolism; Signal Transduction/physiology; Two-Hybrid System Techniques; p38 Mitogen-Activated Protein Kinases/genetics; p38 Mitogen-Activated Protein Kinases/metabolism
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
MOUSE:MAPK5	located_in	GO:0005737: cytoplasm	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
MOUSE:MAPK5	located_in	GO:0005634: nucleus	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
MOUSE:MAPK5	enables	GO:0004674: protein serine/threonine kinase activity	ECO:0000314: direct assay evidence used in manual assertion		F		Seeded From UniProt	complete
MOUSE:MAPK5	enables	GO:0051019: mitogen-activated protein kinase binding	ECO:0000353: physical interaction evidence used in manual assertion	UniProtKB:Q61532	F		Seeded From UniProt	complete
MOUSE:MK06	located_in	GO:0005737: cytoplasm	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
MOUSE:MK06	located_in	GO:0005634: nucleus	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
MOUSE:MK06	enables	GO:0004707: MAP kinase activity	ECO:0000314: direct assay evidence used in manual assertion		F		Seeded From UniProt	complete
MOUSE:MK06	involved_in	GO:0006468: protein phosphorylation	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
MOUSE:MK06	enables	GO:0019901: protein kinase binding	ECO:0000353: physical interaction evidence used in manual assertion	UniProtKB:O54992	F		Seeded From UniProt	complete

References

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