Identification, interactions, and specificity of a novel MAP kinase kinase, MKK7

Abstract

The mitogen activated protein kinase (MAP kinase) cascade has emerged as an evolutionarily conserved element in the transduction of a wide variety of extracellular signals. In mammals, at least three distinct pathways have been identified. These include ERKs, activated by growth factors and other mitogenic stimuli; JNKs, activated by stressful stimuli such as cytokines, UV radiation and protein synthesis inhibitors; and p38 MAP kinases, which are also responsive to stress-related stimuli. Although the existence of distinct MAP kinase pathways has been suggested to provide a basis for signaling specificity, it remains unclear how this might be achieved at a molecular level. One shared characteristic of MAP kinases is their requirement for phosphorylation on both threonine and tyrosine within a TXY motif for activation. These reactions are catalyzed by a family of kinases termed MAP kinase kinases (MKKs). Multiple MKKs have been shown to share specificity for a particular MAP kinase.In order to further understand the activation, localization and substrate specificity of MKKs, a yeast two-hybrid library screen with MKK1 was performed. Results from this screen identified a novel MKK, termed MKK7. MKK7 is activated by stresses, including exposure of cells to osmotic shock or inflammatory cytokines such as interleukin-1. MKK7 directly phosphorylates and activates the MAP kinase JNK. Several stress-activated protein kinases are capable of activating MKK7, indicating that MKK7 may function in multiple stress-mediated signaling pathways. MKK7 is a murine homolog of Drosophila Hemipterous (Hep) and can functionally rescue Hep deficient flies. Loss of function of Hep in Drosophila inhibits dorsal closure, a morphogenetic movement during late embryogenesis.The human homolog of a Drosophila coiled-coil protein, BicaudalD (hBicD) associates specifically with MKK7, and this association is dependent on hBicD phosphorylation. In Drosophila BicD functions to properly localize developmental factors within the oocyte and the developing embryo. One role of hBicD may be to localize MKK7, or components of an MKK7 signaling pathway, to discrete locations within the cell. The properties of MKK7 demonstrate it may be important for normal development and for mediating stress responses, and these events may be partially regulated by its precise cellular localization.