High impact information on PARD6A

• Recently, we have come to understand how regulation of the Par6 interactome by extracellular cues such as integrin and transforming growth factor beta signalling regulates cell motility and tight junction dissolution [1].
• The critical regulator of polarity, Par6, is a key member of a multi-component polarity complex that controls a variety of cellular processes such as asymmetric cell division, establishment of epithelial apico-basal polarity, and polarized cell migration [1].
• Rho GTPases also capture and stabilise microtubules through their effectors (e.g. IQGAP1, mDia and Par6) near the cell cortex, leading to polarised cell morphology and directional cell migration [2].
• Cell polarity: Par6, aPKC and cytoskeletal crosstalk [3].
• Recently, information has come at an impressive pace, both with regard to previously identified targets for Cdc42 that regulate the actin cytoskeleton (e.g. WASP) and cellular stress pathways (e.g. PAK) and with regard to newly identified targets such as the coatomer protein complex and PAR6 [4].

Biological context of PARD6A

• PAR-6 contains a PDZ domain and in C. elegans it has been shown to be crucial for the asymmetric cleavage and establishment of cell polarity during the first cell divisions in the growing embryo [5].
• The cell polarity protein PAR3, conserved from the nematode to the vertebrate, forms a complex with PAR6 and atypical protein kinase C (aPKC), and the protein complex occurs at the tight junctions in mammalian epithelial cells [6].
• This phenotype relied on the presence of CRB3 four last amino acids (ERLI) that are involved in a direct interaction with Par6, a regulator of epithelial polarity and tight junction formation [7].
• CRB3 binds directly to Par6 and regulates the morphogenesis of the tight junctions in mammalian epithelial cells [7].
• Partitioning-defective protein 6 (Par6) was detected in human cDNA libraries of different adult insulin-sensitive tissues [8].

Anatomical context of PARD6A

• Similarly, overexpression of Par6 in MDCK cells inhibits localization of PALS1 to the tight junction [9].
• Furthermore, co-immunoprecipitation experiments, employing Cos-1 cells, demonstrated that mammalian PAR-6 and PAR-3 formed a direct complex [5].
• We found that, in epithelial Madin-Darby canine kidney cells (MDCK), endogenous PAR-6 was present in the tight junctions, as judged from its co-localisation with the tight junction protein ZO-1, however, PAR-6 was also detected in the cell nucleus [5].
• We therefore studied the effects of Par6 overexpression in C2C12 murine myoblasts [8].
• PAR-6 is essential for asymmetric division of the Caenorhabditis elegans zygote [10].

Associations of PARD6A with chemical compounds

• ATG-mediated inhibition of transformation is relieved by expression of constitutively active Rac1, consistent with a mechanism at the level of the interaction between PKCiota and Par6 [11].
• Here we identify an evolutionarily conserved region in the amino terminus of PALS1 as the Par6 binding site and identify valine and aspartic acid residues in this region as essential for interacting with the PDZ domain of Par6 [12].
• Mutation of Cys-69 of PKCiota to isoleucine or valine, residues frequently found at this position in other PB1 domains, has little or no effect on the affinity of PKCiota for Par6 but confers resistance to ATM-mediated inhibition of Par6 binding [13].
• We recently identified the gold compound aurothiomalate (ATM) as a potent inhibitor of the Phox and Bem1p (PB1)-PB1 domain interaction between protein kinase C (PKC) iota and the adaptor molecule Par6 [13].

Physical interactions of PARD6A

• The encoded protein of 1,205 amino acids contains a region homologous to the aPKC-binding domain of PAR3alpha, another human homologue previously identified, and three PDZ domains; the first PDZ domain of PAR3alpha is considered to interact with PAR6 [6].
• Unexpectedly, in contrast to other PAR3s found in various species, PAR3beta is incapable of binding to any isotypes of PAR6 or aPKC [6].
• Uniquely, Par6 possesses a semi-CRIB motif that is not sufficient for binding to Cdc42 [14].

Other interactions of PARD6A

• Here we report the crystal structure of a complex between Cdc42 and the Par6 GTPase-binding domain [14].
• The small G protein Cdc42 is a key regulator of polarity in other systems, and recently it has been shown to interact with the mammalian homolog of PAR-6 [15].
• A cell polarity complex consisting of partitioning defective 3 (PAR-3), atypical protein kinase C (aPKC) and PAR-6 has a central role in the development of cell polarity in epithelial cells [16].
• Both PAR-3 and PAR-6 associate directly with the adherens junction protein vascular endothelial cadherin (VE-cadherin) [16].
• Recent studies have shown that polarity proteins such as mammalian Partitioning-defective 6 (Par6), atypical protein kinase C (aPKC) and mammalian Discs large 1 (Dlg1) are crucial not only for epithelial apico-basal polarity, but also for directional movement [17].

References