page 689, Smith et al. identify a simple, yet until now elusive, mechanism by which cells uncouple MAPK's proliferative effects from its other functions.
The strategy is based on compartmentalization. To bring about cell division, MAPK phosphorylates nuclear substrates such as Elk-1. But its nonproliferation substrates are cytoplasmic. So the simple fix to stop division in differentiated cells, as Smith and colleagues show, is to prevent MAPK from entering the nucleus. The group uses retinoic acid to induce differentiation in both embryonic stem cells and an embryonic carcinoma cell line. After treatment, activated MAPK—which had resided in both the nucleus and cytoplasm of undifferentiated cells—was restricted to the cytoplasm, as were its phosphorylated substrates.
Since nuclear export is not required for this change in localization, MAPK import must be blocked somehow. An intact cytoskeleton is required for the nuclear exclusion, so the authors speculate that differentiation changes actin and microtubule dynamics and cellular trafficking such that MAPK is continually transported away from nuclear pores. ▪