Mechanism and Regulation of ERK2 Subcellular Localization

Dynamic changes in the localization of activated proteins can be obligatory events in signaling networks that control cell behavior. ERK1/2 activation contributes to regulated processes such as proliferation, differentiation and survival through the phosphorylation of multiple nuclear and cytoplasmic substrates. The pleiotropic effects of ERK1/2 activation suggest that regulated compartmentalization of the kinases and substrates may contribute to the fidelity of phenotypic changes in response to specific cell stimuli. Therefore, elucidating the mechanism of translocation as well as how this process is controlled is important for understanding how MAP kinases transmit signals. In vitro studies using a permeabilized cell system indicate that nuclear import of ERK2 is not regulated by soluble transport factors, but requires access to nucleoporins. While this process is not influenced by classical import machinery, it can be modulated by anchoring proteins that bind to ERK2 and sequester the kinase in the cytoplasm. One of these proteins, PEA-15, prevents ERK2 import in an in vitro system by inhibiting the kinases' ability to interact with nucleoporins. In vivo assays of phosphorylated ERK1/2 show discrete subcellular localization patterns in response to different stimuli that are independent of the level of ERK1/2 activation. Under conditions in which ERK1/2 is concentrated in the cytoplasm, the nuclear substrate of the kinase, c-Fos, is not expressed, while the cytoplasmic substrate of ERK1/2, p90RSK, is phosphorylated.