Mitogen-activated 3p kinase is active in the nucleus.
The MAPK-activated kinase 3pK (chromosome 3p kinase), also known as MAPKAPK-3, is a member of a family of kinases that are activated by more than one mitogen-activated protein kinase (MAPK). 3pK is unique since it was shown to be activated by three members of the MAPK family, namely extracellular-signal-regulated kinase (ERK), p38, and Jun-N-terminal kinase (JNK). Accordingly, 3pK is highly activated both by mitogens and by stress-inducing agents or proinflammatory cytokines. Studies utilizing dominant interfering mutants and pharmacological agents revealed that upon mitogenic stimulation, 3pK is exclusively activated via the classical MAPK cascade, while stress-induced activation of 3pK is mainly mediated by p38. The mechanism defining the specificity of kinase action in response to mitogenic versus stress activation remains unknown. Here we show that 3pK is transported to the cytoplasm upon both stress and mitogenic stimulation. While kinetics of nuclear export are similar in both situations, the activation pattern differs substantially. In the mitogenic situation, active 3pK remains in the nucleus for a significant time and there may fulfill mitogen-specific functions. These data not only show that nuclear export of the kinase is mechanistically uncoupled from its activation, but also provide a novel mechanism by which cells may modulate enzyme activity toward a stimulus-specific response.
Institut für Molekulare Medizin (IMM), Heinrich-Heine-Universität Düsseldorf, D-40225 Düsseldorf, Germany.
Vera
V
Zakowski
Georgios
G
Keramas
Karin
K
Kilian
Ulf R
UR
Rapp
Stephan
S
Ludwig
D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D003593:Cytoplasm / Q000201:enzymology; D004789:Enzyme Activation / Q000502:physiology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D008934:Mitogens / Q000494:pharmacology*; D009154:Mutation / Q000187:drug effects / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D013312:Stress, Physiological / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
D047908:Intracellular Signaling Peptides and Proteins; D008934:Mitogens; C098416:MAP-kinase-activated kinase 3; D017346:Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases