Disease relevance of aPKC

• Atypical protein kinase C in neurodegenerative disease I: PKMzeta aggregates with limbic neurofibrillary tangles and AMPA receptors in Alzheimer disease [1].
• Although several recent works support a causative role for aPKCiota overexpression in human carcinomas, our results suggest a key role for aPKCzeta in apical-basal polarity loosening, a mechanism that seems to be driven by changes in protein localization rather than in protein abundance [2].

High impact information on aPKC

• The apical determinants aPKC and dPatj regulate Frizzled-dependent planar cell polarity in the Drosophila eye [3].
• Our data suggest that AurA, aPKC, Numb, and Notch function in a pathway that involved a series of negative genetic interactions [4].
• Baz/Par-6/aPKC are therefore not essential for axon specification in Drosophila [5].
• Moreover, we found that these transmembrane proteins differentially regulate the intracellular localization of GSK3beta and aPKC at cell junctions [6].
• At the postsynapse, aPKC regulates the synaptic cytoskeleton by controlling the extent of Actin-rich and MT-rich areas [7].

Biological context of aPKC

• aPKC-mediated phosphorylation regulates asymmetric membrane localization of the cell fate determinant Numb [8].
• Drosophila aPKC regulates cell polarity and cell proliferation in neuroblasts and epithelia [9].
• These results suggest a model in which phosphorylation of Numb by aPKC regulates its polarized distribution in epithelial cells as well as during asymmetric cell divisions [8].
• Collectively, these results demonstrate the conservation of the p62-aPKC complex for the control of innate immunity signal transduction in Drosophila melanogaster [10].
• We propose that a high-affinity binding site is asymmetrically distributed by aPKC and Lgl and is responsible for asymmetric localization of cell-fate determinants during mitosis [11].

Anatomical context of aPKC

• Here, we show that Drosophila aPKC zygotic null mutants survive to mid-larval stages, where they exhibit defects in neuroblast and epithelial cell polarity [9].
• In light of this functional conservation, we examined the potential role of baz and DaPKC in the regulation of oocyte polarity [12].
• Our analyses reveal germ-line autonomous roles for baz and DaPKC in the establishment of initial anterior-posterior polarity within germ-line cysts and maintenance of oocyte cell fate [12].
• Here we show that at Drosophila glutamatergic synapses, aPKC controls the formation and structure of synapses by regulating microtubule (MT) dynamics [7].
• New synaptic bouton formation is disrupted by misregulation of microtubule stability in aPKC mutants [7].

Associations of aPKC with chemical compounds

• Bazooka and atypical protein kinase C are required to regulate oocyte differentiation in the Drosophila ovary [12].
• In cultured cell lines and in mouse brain, aPKC, mPar-6C and Mlgl form a multiprotein complex in which Mlgl is targeted for phosphorylation on conserved serine residues [13].
• Here, we demonstrate that human Par-1b (hPar-1b) interacts with and is negatively regulated by atypical PKC. hPar-1b is phosphorylated by aPKC on threonine 595, a residue conserved in Par-1 orthologs in mammals, worms, and flies [14].

Physical interactions of aPKC

• PAR-6 is a direct effector of Rho family GTPases and binds to and regulates aPKC [15].
• Surprisingly, we found that Baz localizes to an apical domain below its typical binding partners atypical protein kinase C (aPKC) and partitioning defective (PAR)-6 as the Drosophila epithelium first forms [16].
• In Drosophila neuroblasts, the apical DmPar6/DaPKC complex inhibits Lethal giant larvae (Lgl) to promote the basal localization of fate determinants [17].
• We show that Dap160 directly interacts with aPKC, stimulates aPKC activity in vitro and colocalizes with aPKC at the apical cortex of embryonic neuroblasts [18].

Regulatory relationships of aPKC

• In addition, we show that Baz and Par-6 are also expressed at synapses and that their synaptic localization depends on aPKC activity [7].
• At the presynapse, aPKC regulates the stability of MTs by promoting the association of the MAP1Brelated protein Futsch to MTs [7].
• Moreover, the phenotypic effect of overexpressing wild-type Crumbs is suppressed by reducing DaPKC activity [19].

Other interactions of aPKC

• Therefore, whereas BAZ, DaPKC, and PAR-1 are functionally conserved in establishing oocyte polarity, the regulatory relationships among these genes are not well conserved, indicating these molecules function differently in different cellular contexts [12].
• Expression of a carboxy-terminal fragment plus the third PDZ domain of Par-3 partially rescues junction assembly, but neither Par-6 nor aPKC binding is required [20].
• DaPKC-dependent phosphorylation of Crumbs is required for epithelial cell polarity in Drosophila [19].
• Lgl, Pins and aPKC regulate neuroblast self-renewal versus differentiation [21].
• Both eye-PKC and DaPKC are differentially localized through tethering to multimolecular complexes [22].

Analytical, diagnostic and therapeutic context of aPKC

• 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 [23].

References