The mitogen-activated protein kinase (MAPK) 1 pathways transduce various extracellular stimuli into distinct intracellular responses. The core component of such a MAPK module is a set of three sequential kinases that are evolutionarily conserved in eukaryotes from unicellular yeast to plants and animals. In mammalian cells, three distinguishable MAPK modules have been well described; they are the extracellular signalregulated kinases 1 and 2 (ERK1/2), the c-Jun N-terminal kinase (JNK), and the p38 pathways. The MAPK pathways regulate cell growth, differentiation, adaptation to the environment, and apoptosis in response to a great number of stimuli, including cytokines and various stresses (1-3). The MAPKs also control numerous regulatory processes during development and homeostasis (4 -6).Our laboratory previously cloned two MAPK kinase kinases, designated MEKK2 and MEKK3 (7). MEKK2 and MEKK3 are extremely homologous (94% conserved) in their catalytic domains, but their regulatory N-terminal sequences are quite divergent, with only 65% homology, predicting that they perform similar as well as different cellular tasks. In this regard, Schaefer et al. (8) showed that T cell MEKK2 but not MEKK3 is activated and translocates to the plasma membrane at the contact with antigen-loaded presenting cells. Thus, although MEKK2 and MEKK3 are both mediators of signal transduction to the MAPK pathways, they are subject to stimulus-and cell type-specific regulation. A differential involvement of MEKK2 and MEKK3 in cellular signaling has also been demonstrated by our recent finding that MEKK2 but not MEKK3 regulates the activity of the protein kinase C-related kinase PRK2 (9).Big mitogen-activated protein kinase 1 (BMK1)/ERK5 was recently cloned as a novel member of the MAPK family (10, 11). Like ERK1/2, BMK1/ERK5 has a TEY sequence in its dual phosphorylation motif; however, other structural features such as a large regulatory C terminus and a unique loop 12 domain distinguish BMK1/ERK5 from ERK1/2 and other MAP kinases (10). This predicts that the regulation and function of BMK1/ ERK5 are distinct from those of other MAPKs. In this regard, Zhou et al. (11) showed that BMK1/ERK5 interacts specifically with MEK5 but not its closely related MAPK kinases MEK1 and MEK2, suggesting that MEK5/BMK1 represents a separate signaling module. Indeed, MEK5 selectively phosphorylates and activates BMK1/ERK5 (12, 13), and its activity is required for the activation of BMK1/ERK5 induced by extracellular signals, including growth factors, serum, oxidative stress, and hyperosmolarity (13,14). Consistent with the notion that MEK5/BMK1 lies in a signal transduction pathway