The functional importance of spatially and temporally regulating ERK activation was originally observed in rat PC12 cells, where it was found that the transient activation of ERK promoted cell proliferation, whereas sustained activation led to a significant accumulation of nuclear ERK and cell differentiation ( 2, 7). The components of MAPK pathways are often found associated with regulatory or scaffold proteins that can enhance signaling specificity and localize the pathway to distinct cell compartments ( 2). This consists of RAS GTPase, RAF (a MAPK kinase kinase), and MEK, which activates ERK by phosphorylation on Thr and Tyr residues within a Thr-Glu-Tyr motif located in its activation loop ( 2). The ERK MAPK pathway is activated by diverse stimuli, including growth factors, hormones, and cytokines, and similar to other MAPK pathways features a multitiered signaling module. In this issue, Plotnikov and coworkers report that casein kinase 2 (CK2) directly phosphorylates ERK and promotes its nuclear import, thus uncovering a novel point of regulation in the ERK MAPK pathway ( 8). While a number of studies have addressed the spatial regulation of ERK in cells, and in particular how it gets targeted to the nucleus ( 13), our understanding of the molecular mechanisms involved remains incomplete. ERK phosphorylates substrates that reside throughout the cell however, many ERK targets are nuclear and mediate changes in gene expression ( 2, 7).

The misregulation of ERK signaling is implicated in several disorders, including cancer, immune disease, and neurodegenerative disease ( 2). The extracellular signal-regulated kinase (ERK) is a member of the evolutionarily conserved mitogen-activated protein kinase (MAPK) family and is a key regulator of many cellular processes, including growth, differentiation, cell survival, and the immune response ( 2).

Ck2 found a new kingdom