Disease relevance of PARD3

• Down-regulated expression of atypical PKC-binding domain deleted asip isoforms in human hepatocellular carcinomas [1].

High impact information on PARD3

• PAR-3 is required for Cdc42-induced Rac activation, but is not essential for lamellipodia formation itself [2].
• Furthermore, pVHL interacts with the Par3-Par6-atypical PKC complex, suggesting a mechanism for linking polarity pathways to microtubule capture and ciliogenesis [3].
• Our data suggest that the ASIP/PAR-3-aPKC complex is tethered to tight junctions via its association with JAM, indicating a potential role for JAM in the generation of cell polarity in epithelial cells [4].
• In fibroblasts and CHO cells overexpressing JAM, endogenous ASIP is recruited to JAM at sites of cell-cell contact [4].
• Ectopic expression of MARK2 caused phosphorylation of tau (S262) and led to loss of axons, and this phenotype was rescued by expression of PAR-3, PAR-6, and aPKC [5].

Biological context of PARD3

• These data suggest that aPKC binding or phosphorylation is not required for targeting of Par3/Par3L to cell-cell contacts [6].
• Exon 17b deleted asip mRNAs expressed ubiquitously in normal human tissues, including liver, on RT-PCR analysis [1].
• Human asip is a single copy gene consisting of at least 26 exons and localizing in human chromosome 10, band p11.2, with some extraordinarily long introns [1].
• Over-expression of PAR-3 suppresses contact-mediated inhibition of cell migration in MDCK cells [7].
• Down-regulation of PAR3/PAR6/aPKC complex also leads to EMT [8].

Anatomical context of PARD3

• Furthermore, co-immunoprecipitation experiments, employing Cos-1 cells, demonstrated that mammalian PAR-6 and PAR-3 formed a direct complex [9].
• Although all of the Par3L/Par3 isoforms can associate with tight junctions in epithelial cells, they show different binding properties [6].
• Both PAR-3 and PAR-6 associate directly with the adherens junction protein vascular endothelial cadherin (VE-cadherin) [10].
• A common effect was an increase in the expression of JAM-A, AF-6, and PAR-3 that correlated with a redistribution of actin filaments [11].
• During the polarization of Caco-2 cells, the expression of PAR-3 increases as do those of other cell-cell junction proteins, whereas the expression of sPAR-3 decreases [12].

Associations of PARD3 with chemical compounds

• Asip/Par-3/Bazooka are PDZ-motif containing proteins that localize asymmetrically to the cell periphery and play a pivotal role in cell polarity and asymmetric cell division [1].
• The co-expression of a dominant negative mutant of Rac1 and the addition of nocodazole strongly antagonize the effect of PAR-3 over-expression, suggesting the involvement of Rac1 activation and microtubule polymerizations [7].

Physical interactions of PARD3

• 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 [13].

Regulatory relationships of PARD3

• We review studies on the polarity of developing cerebellar granule, showing that the centrosome localizes to the pole of the neuron that extrudes the nascent axon, and the Rho GTPase Cdc42 (cell division cycle 42) activates the mPar6alpha/Par3 (Par for partitioning defective) complex to coordinate actin dynamics in the growth cone [14].

Other interactions of PARD3

• 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 [10].
• Junctional adhesion molecule (JAM)-A is an integral membrane protein at tight junctions of epithelial cells which associates with the cell polarity protein PAR-3 [15].
• RT-PCR showed that epithelial cells express the thrombin receptors protease-activated receptor (PAR)-1, PAR-3, and PAR-4 [16].

Analytical, diagnostic and therapeutic context of PARD3

• However, plasma clearance rates (PCR, 5.37 mL/h . 100 g body wt) and plasma appearance rates (PAR3 = PCR x [T3] plasma = 36.3 ng/h . 100 g body wt) were quite different than these indices in rat and human and 5 to 50 times larger than values reported for rainbow trout [17].

References