Scaffolding by ERK3 regulates MK5 in development.
Extracellular-regulated kinase 3 (ERK3, MAPK6) is an atypical member of the ERKs, lacking the threonine and tyrosine residues in the activation loop, carrying a unique C-terminal extension and being mainly regulated by its own protein stability and/or by autophosphorylation. Here we show that ERK3 specifically interacts with the MAPK-activated protein kinase 5 (MK5 or PRAK) in vitro and in vivo. Expression of ERK3 in mammalian cells leads to nuclear-cytoplasmic translocation and activation of MK5 and to phosphorylation of both ERK3 and MK5. Remarkably, activation of MK5 is independent of ERK3 enzymatic activity, but depends on its own catalytic activity as well as on a region in the C-terminal extension of ERK3. In mouse embryonic development, mRNA expression patterns of ERK3 and MK5 suggest spatiotemporal coexpression of both kinases. Deletion of MK5 leads to strong reduction of ERK3 protein levels and embryonic lethality at about stage E11, where ERK3 expression in wild-type mice is maximum, indicating a role of this signalling module in development.
Schumacher
Stefanie
S
Medical School Hannover, Institute of Biochemistry, Hannover, Germany.
Laass
Kathrin
K
Kant
Shashi
S
Shi
Yu
Y
Visel
Axel
A
Gruber
Achim D
AD
Kotlyarov
Alexey
A
Gaestel
Matthias
M
D000818:Animals; D002460:Cell Line; D004622:Embryo, Mammalian / Q000033:anatomy & histology / Q000502:physiology*; D047108:Embryonic Development / Q000502:physiology*; D004789:Enzyme Activation; D006801:Humans; D017403:In Situ Hybridization; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D018345:Mice, Knockout; D048053:Mitogen-Activated Protein Kinase 6 / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D020798:Two-Hybrid System Techniques
D047908:Intracellular Signaling Peptides and Proteins; D011993:Recombinant Fusion Proteins; C111049:MAP-kinase-activated kinase 5; D017346:Protein Serine-Threonine Kinases; D048053:Mitogen-Activated Protein Kinase 6