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.