Two co-existing mechanisms for nuclear import of MAP kinase: passive diffusion of a monomer and active transport of a dimer

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Abstract
In response to extracellular stimuli, mitogen‐activated protein kinase (MAPK, also known as ERK) translocates from the cytoplasm to the nucleus. MAP kinase kinase (MAPKK, also know as MEK), which possesses a nuclear export signal (NES), acts as a cytoplasmic anchor of MAPK. Here we show evidence that tyrosine (Tyr190 in Xenopus MPK1/ERK2) phosphorylation of MAPK by MAPKK is necessary and sufficient for the dissociation of the MAPKK‐MAPK complex, and that the dissociation of the complex is required for the nuclear translocation of MAPK. We then show that nuclear entry of MAPK through a nuclear pore occurs via two distinct mechanisms. Nuclear import of wild‐type MAPK (mol. wt 42 kDa) was induced by activation of the MAPK pathway even in the presence of wheat germ agglutinin or dominant‐negative Ran, whereas nuclear import of β‐galactosidase (β‐gal)‐fused MAPK (mol. wt 160 kDa), which occurred in response to stimuli, was completely blocked by these inhibitors. Moreover, while a dimerization‐deficient mutant of MAPK was able to translocate to the nucleus upon stimulation, this mutant MAPK, when fused to β‐gal, became unable to enter the nucleus. These results suggest that monomeric and dimeric forms of MAPK enter the nucleus by passive diffusion and active transport mechanisms, respectively.