MKK7 IS A STRESS-ACTIVATED MITOGEN-ACTIVATED PROTEIN-KINASE KINASE FUNCTIONALLY RELATED TO HEMIPTEROUS

Exposure of mammalian cells to stressful stimuli results in activation of the c-Jun NH2-terminal kinase (JNK)/stress-activated protein kinas es (SAPKs), a family of protein kinases related to mitogen-activated p rotein (MAP) kinase, JNK/SAPKs are activated by specific MAP kinase ki nases (MKKs), one of which, MKK4/SEK1, has been characterized extensiv ely, In Drosophila, the JNK/SAPK Basket (Bsk) and the MKK Hemipterous (Hep), are important for embryonic development, Loss of function of ei ther gene inhibits dorsal closure, a morphogenetic movement in which t he edges of the embryonic ectoderm move together over the amnioserosa. There is evidence that the Rho GTPases Rac and Cdc42 are also require d for dorsal closure, suggesting that Rac or Cdc42 may regulate Hep an d Bsk, We have identified MKK7, a murine homolog of Hep. MKK7 function ally rescues hep mutant flies, In fibroblasts, MKK7 is activated by st ress and by the GTPase Rac1. MKK7 directly phosphorylates and activate s JNK/SAPK. Thus, MKK7 is a homolog of hep and functions in a conserve d signaling pathway involving JNK/SAPK and the GTPase Rac1.