Non-regulated and stimulated mechanisms cooperate in the nuclear accumulation of MEK1

MEKs, which operate within the ERK cascade, shuttle into the nucleus, but a re rapidly exported from this location, forming an apparent cytosolic distr ibution both before and after stimulation. Two different mechanisms have be en proposed for the nuclear translocation of MEKs. One of them involves a c onstant and nonregulated shuttling of MEKs into the nucleus operating both before and after mitogenic stimulation. The other mechanism seems to requir e the activity of MEKs and is facilitated in response to mitogenic stimulat ion. Here we show that these two mechanisms may coexist in the same cells. We found that leptomycin B (LMB), a potent inhibitor of nuclear export, ind uces a nuclear accumulation of MEKs, and this was significantly facilitated by stimulation of LMB-treated cells with EGF, TPA and peroxovanadate. The EGF-stimulated, but not the LMB-induced translocation was attenuated by MEK inhibitors and by using inactive forms of MEK1. We also show that LMB slig htly activates the ERK cascade, but this activity only partially induces th e nuclear accumulation of MEKs in cells treated by LMB alone. Thus, MEKs tr anslocate into the nucleus by a combination of nonregulated and stimulated processes that contribute to the nuclear translocation of MEKs either in re sting cells or upon mitogenic stimulation.