A conserved signal transduction pathway regulating the activity of the rel-like proteins dorsal and NF-kappa B.

Intracellular signal transduction plays a critical role in a number of invertebrate patterning processes. In recent years it has been shown that many steps in these processes require homologues of proteins that transduce signals in cultured mammalian cells. Knowledge of the biochemical function of the vertebrate proteins has made it easier to define the invertebrate signaling pathways. In turn, studies in Caenorhabditis elegans and Drosophila have enabled the identification of new pathway components, as well as provided insight into signaling mechanisms. As an example, I consider here the establishment of dorsoventral polarity in the Drosophila embryo and its relationship to a mammalian signal transduction pathway. The establishment of the dorsoventral axis in Drosophila depends on the spatially regulated subcellular localization of the transcription factor dorsal (for reviews, see Govind and Steward, 1991; St. Johnston and Niisslein-Volhard, 1992). During oogenesis, dorsal protein is deposited uniformly in the egg cytoplasm, where it is held through an interaction with the cactus protein. Soon after fertilization, a ventrally localized, extracellular ligand acts through the transmembrane receptor Toll to overcome the inhibitory effect of cactus and thereby direct dorsal protein into nuclei (Hashimoto et al., 1988; Roth et al., 1989; Rushlow et al., 1989; Steward, 1989; Stein et al., 1991). When present at high concentrations within nuclei, dorsal protein activates ventral-specific genes, while at the same time repressing dorsal-specific loci. The graded distribution of the dorsal protein in nuclei across the embryo can thus define the dorsoventral axis (for further discussion, see Jiang and Levine, 1993). In mammalian cells, the subcellular localization of the transcription factor NF-KB is controlled in a manner very similar to that observed for dorsal. An inhibitory protein, IKB, binds stably to NF-KB (Baeuerle and Baltimore, 1988b). This interaction masks a nuclear localization signal (NLS) in NF-KB; the complex therefore remains cytoplasmic (Beg et al., 1992). Activating signals received at the cell surface cause dissociation of the protein-protein complex, freeing NF-KB for translocation into nuclei (Baeuerle and Baltimore, 1988a). Once nuclear, NF-KB, like dorsal, acts as a regulator of a program of gene expression. At least three components of the dorsal and NF-KB signaling pathways share structural as well as functional similarity (Table 1). First, dorsal and NF-KB belong to a family of DNA-binding proteins that includes the oncoprotein v-rel and its cellular homologue, c-rel (for reviews, see Blank et al., 1992; Nolan and Baltimore, 1992; Rushlow and Warrior, 1992). These proteins have in common a conserved 300 amino acid region, the relhomology domain, that contains an NLS, a DNA-binding region, and a conserved, consensus phosphorylation site for the cAMP-dependent protein kinase (PKA). Second, cactus and the lKBa isoform each contain multiple ankyrin repeats that mediate the protein-protein interactions required for their function (Davis et al., 1991; Haskill et al., 1991; Geisler et al., 1992; Kidd, 1992). Third, one of the extracellular signals that can activate NF-KB, interleukin-1 (IL-1), acts through a receptor with structural similarity to the Drosophila Toll protein (Osborn et al., 1989; Shirakawa et al., 1989). The type I IL-1 receptor and Toll, each of which has a single membrane-spanning segment, are similar in sequence over 217 amino acids in their intracellular domains (Hashimoto et al., 1988; Sims et al., 1988; Gay and Keith, 1991; Schneider et al., 1991). Although the intracellular domains share only 26% amino-acid identity, conserved residues are the site of inactivating mutations in both receptors, supporting the hypothesis that the IL-1 receptor and Toll carry out homologous functions (Schneider et al., 1991; Heguy et al., 1992).