High impact information on par-6

• Cdc42 regulates the Par-6 PDZ domain through an allosteric CRIB-PDZ transition [1].
• Here, we show that the PDZ protein interaction domain from the cell polarity protein Par-6 is regulated by the Rho GTPase Cdc42 [1].
• Baz/Par-6/aPKC are therefore not essential for axon specification in Drosophila [2].
• Epithelial cells lose their apical-basal polarity in DmPAR-6 mutants, asymmetric cell divisions in neuroblasts are misorientated, and the proteins Numb and Miranda do not segregate correctly into the basal daughter cell [3].
• Here we show that the PDZ-domain protein DmPAR-6 cooperates with Bazooka for both of these functions [3].

Biological context of par-6

• Requirement for Par-6 and Bazooka in Drosophila border cell migration [4].
• Interaction of Par-6 and Crumbs complexes is essential for photoreceptor morphogenesis in Drosophila [5].
• The distributions of several transmembrane proteins required for migration were abnormal following Par-6 or Par-3/Bazooka downregulation, possibly accounting for the migration defects [4].
• These results suggest a mechanism by which the requirement for a C terminus can be readily bypassed by PDZ ligands and reveal a complex set of cooperative and competitive interactions in Par-6 that are likely to be important for cell polarity regulation [6].
• DmPAR-6 directs epithelial polarity and asymmetric cell division of neuroblasts in Drosophila [3].

Anatomical context of par-6

• In vivo analysis performed in cell cultures and in the Drosophila embryo show that the cytoplasmic domain of Crumbs can recruit DmPar-6 and DaPKC to the plasma membrane [7].
• These results suggest that the interaction of Crb and Par-6 complexes is required for the organization and maintenance of apical membranes and AJs of photoreceptors [5].
• Baz, Par-6 and aPKC are not required for axon or dendrite specification in Drosophila [2].
• In the absence of DmPAR-6, Bazooka fails to localize apically in neuroblasts and epithelial cells, and is distributed in the cytoplasm instead [3].
• Here, we show that the homologs of PAR-3 (Bazooka) and PAR-6 are also required to maintain oocyte fate [8].

Associations of par-6 with chemical compounds

• Computer modelling in combination with in vitro studies reveals similar binding affinities of Drosophila Crumbs for the PDZ domains of Stardust and DmPar-6 [7].
• AJ assembly is closely coupled to Baz positioning, whereas aPKC and PAR-6 are positioned separately [9].

Physical interactions of par-6

• Here we show by in vitro analysis that, similar as in vertebrates, the single PDZ domain of Drosophila DmPar-6 can bind to the four C-terminal amino acids (ERLI) of the transmembrane protein Crumbs [7].
• We further demonstrate that Dlt directly binds to Par-6, providing a molecular basis for the mutual dependence of the two complexes [5].
• PAR-6 is a direct effector of Rho family GTPases and binds to and regulates aPKC [10].

Co-localisations of par-6

• DmPAR-6 colocalizes with Bazooka at the apical cell cortex of epithelial cells and neuroblasts, and binds to Bazooka in vitro [3].

Regulatory relationships of par-6

• In addition, we show that Baz and Par-6 are also expressed at synapses and that their synaptic localization depends on aPKC activity [11].
• Apical localization of Par-6 requires its interaction with activated Cdc42 and dominant-active or dominant-negative Cdc42 disrupt epithelial polarity, suggesting that activation of this GTPase is crucial for the establishment of epithelial polarity [12].

Other interactions of par-6

• We have also characterized, in more detail, the amino terminus of Drosophila Stardust and demonstrate that the interaction mechanism between Stardust and Drosophila Par6 is evolutionarily conserved [13].
• We show here that polarity is established shortly after cellularization when Par-6 and the atypical protein kinase C concentrate on the apical side of the newly formed cells [12].
• Cdc42 binds to a CRIB domain adjacent to the PDZ domain, increasing the affinity of the Par-6 PDZ for its carboxy-terminal ligand by approximately 13-fold [1].
• Bazooka and PAR-6 are required with PAR-1 for the maintenance of oocyte fate in Drosophila [8].

Analytical, diagnostic and therapeutic context of par-6

• Here we report the molecular cloning of par-6 and the immunolocalization of PAR-6 protein [14].

References