A Drosophila MAPKKK, D-MEKK1, mediates stress responses through activationof p38 MAPK

In cultured mammalian cells, the p38 mitogen-activated protein kinase (MAPK ) pathway is activated in response to a variety of environmental stresses. However, there is little evidence from in vivo studies to demonstrate a rol e for this pathway in the stress response. We identified a Drosophila MAPK kinase kinase (MAPKKK), D-MEKK1, which can activate p38 MAPK. D-MEKK1 is st ructurally similar to the mammalian MEKK4/MTK1 MAPKKK. D-MEKK1 kinase activ ity was activated in animals under conditions of high osmolarity. Drosophil a mutants lacking D-MEKK1 were hypersensitive to environmental stresses, in cluding elevated temperature and increased osmolarity. In these D-MEKK1 mut ants, activation of Drosophila p38 MAPK in response to stress was poor comp ared with activation in wild-type animals. These results suggest that D-MEK K1 regulation of the p38 MAPK pathway is critical for the response to envir onmental stresses in Drosophila.