title: Characterization of the atypical MAPK ERK4 and its activation of the MAPK-activated protein kinase MK5.
abstract: The extracellular-regulated kinase (ERK) 4 (MAPK4) and ERK3 (MAPK6) are structurally related atypical MAPKs displaying major differences only in the C-terminal extension. ERK3 is known as an unstable mostly cytoplasmic protein that binds, translocates, and activates the MAPK-activated protein kinase (MK) 5. Here we have investigated the stability and expression of ERK4 and have analyzed its ability to bind, translocate, and activate MK5. We show that, in contrast to ERK3, ERK4 is a stable protein that binds to endogenous MK5. Interaction of ERK4 with MK5 leads to translocation of MK5 to the cytoplasm and to its activation by phosphorylation. In transfected HEK293 cells, where overexpressed catalytically dead ERK3 is able to activate MK5, catalytic activity of ERK4 is necessary for activation of MK5, indicating that ERK4 directly phosphorylates MK5. Interestingly, ERK4 dimerizes and/or oligomerizes with ERK3, suggesting that overexpressed inactive ERK3 recruits active endogenous ERK4 to MK5 for its activation. Hence, ERK3 and ERK4 cooperate in activation of MK5.
authors.affiliation: Institute of Biochemistry, Medical School Hannover, Hannover 30625, Germany.
authors.forename: Shashi
authors.initials: S
authors.lastname: Kant
authors.forename: Stefanie
authors.initials: S
authors.lastname: Schumacher
authors.forename: Manvendra Kumar
authors.initials: MK
authors.lastname: Singh
authors.forename: Andreas
authors.initials: A
authors.lastname: Kispert
authors.forename: Alexey
authors.initials: A
authors.lastname: Kotlyarov
authors.forename: Matthias
authors.initials: M
authors.lastname: Gaestel
mesh_terms: D002460:Cell Line; D004789:Enzyme Activation; D004795:Enzyme Stability; D017353:Gene Deletion; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D048053:Mitogen-Activated Protein Kinase 6 / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D021381:Protein Transport
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C111049:MAP-kinase-activated kinase 5; D017346:Protein Serine-Threonine Kinases; D048053:Mitogen-Activated Protein Kinase 6; D020929:Mitogen-Activated Protein Kinase Kinases