PDZ domain polarity complexes

What are they? Three protein complexes, each containing at least one PDZ protein–protein interaction domain, are critical regulators of cell polarity in animals. Each complex can be referred to by one of its primary components: the Par-3 or Baz complex, including Par-6 and aPKC; the Crb complex, including Sdt; and the Scrib complex, including Dlg. The Lgl protein, which has activities similar to the Scrib complex, seems to physically associate not with the Scrib but with the Baz complex.Are they conserved across species? Yes: orthologous complexes are found in worms, flies and vertebrates. Not only is the composition of the complexes conserved, but there is also remarkable conservation of their localization, particularly in epithelial cells. Nevertheless, the mutant phenotypes caused by defects in components of the complexes vary across species, suggesting that the story may be more complicated.How were they identified? Primarily through genetic screens in model organisms. Mutations of Crb, Sdt and Baz cause polarity defects in Drosophila embryonic epithelia, while those of Par-3 and Par-6 disrupt cytoplasmic partitioning in the early Caenorhabditis elegans zygote. A mammalian Par-3 homolog physically associates with aPKC, while Baz is the fly Par-3 homolog. Dlg and Lgl were first isolated as Drosophila tumor suppressors that cause overgrowth and disorganization of imaginal epithelia. Scrib and its worm ortholog Let-413 were identified in screens for epithelial shape defects.What cells are they active in? All three complexes are required for polarization of the Drosophila embryonic and ovarian epithelia, though some fly epithelia that require the Scrib complex, such as wing imaginal discs, develop well without either the Crb or Baz complex. Worm epithelia require the Scrib complex; requirements for the Baz and Crb complexes have not yet been reported. In zebrafish, mutations in aPKC and Sdt homologs cause disorganization of certain endodermal, mesodermal and retinal epithelia. Outside of epithelia, the Baz and Scrib complexes are both involved in polarization of Drosophila neuroblasts and, later, in organization of the neuromuscular junction. Finally, the Baz complex is required for polarization of both the one-cell worm zygote and the Drosophila oocyte.Where are they found in the cell? In epithelial tissues, the Crb complex is found along the apical-most region of the lateral plasma membrane, corresponding to the tight junction in vertebrates or the marginal zone in Drosophila. The Baz complex is found at either the tight junction or the zonula adherens, while the Scrib complex is found along the basolateral domain. In the fly neuroblast and worm zygote, the Baz complex is polarized along one side of the cell (apical or posterior, respectively). The Scrib complex is localized throughout the cortex of fly neuroblasts. In mature neurons, Scrib and Baz are restricted to synapses. Lgl is broadly associated throughout the cell membrane in most cell types.Do the complexes interact? The three complexes can coordinate polarizing activities through positive and negative cross-regulation, as shown in the fly embryo. This regulation may be mediated by physical interactions amongst members of different complexes, such as that between the mammalian Par-6 and Sdt orthologs. A particularly intriguing case is Lgl, which physically interacts with the Baz complex but whose subcellular localization is controlled by the Scrib complex.How do they function in polarity? The mechanism by which the complexes mediate polarity at the cell biological level is not understood. The PDZ proteins act as scaffolds, without clear effector activities. It is suspected that polarizing activity is mediated by effector partners, such as the kinase aPKC and its substrate Lgl, which may be involved in vesicle transport or cytoskeletal regulation. Other effector partners, particularly those that interface with basic cell biological machinery, remain to be identified.Might they be involved in human disease? Mutations in a human Crb gene, CRB1, cause retinal degeneration in one class of retinitis pigmentosa patients. Indirect evidence hints at a role of the complexes in oncogenesis: Par-6 can potentiate transformation, while Scrib complex proteins are targets of oncovirus-mediated protein degradation. A third possibility is raised by the circletail mutant mouse, which carries a mutation in Scrib and displays severe neural tube defects. Further implication of the PDZ polarity complexes in developmental or pathological defects awaits reverse genetic approaches in vertebrate organisms.Figure 1Localization of PDZ polarity complexes, in relation to a generic epithelial cell. The protein names here and in the text are mostly abbreviations, as follows: Crb, Crumbs; Sdt, Stardust; Baz, Bazooka; aPKC, protein kinase C; Scrib, Scribble; Dlg, discs large; Lgl, lethal giant larvae; AJ, adherens junction.View Large Image | View Hi-Res Image | Download PowerPoint SlideWhere can I find out more?