Disease relevance of PKP1

• Interestingly, patients with tumors in which PKP1 and PKP3 immunoreactivity was reduced or absent exhibited local recurrences or metastases, or both, as well as poor survival [1].
• The recessive simplex types include EB with muscular dystrophy due to abnormal plectin, EB without muscular dystrophy in patients homozygous for K14 gene abnormalities, and skin fragility syndrome, with formation of acantholytic vesicles within the epidermis due to PKP1 gene mutations [2].
• In contrast, all adenocarcinomas contained PKP 2 and-often abundantly-PKP 3 in desmosome-typical pattern, whereas PKP 1 was expressed only in prostate tumors [3].
• Increased expression of delta-catenin/neural plakophilin-related armadillo protein is associated with the down-regulation and redistribution of E-cadherin and p120ctn in human prostate cancer [4].
• The identification of the first congenital defect affecting a desmosome component was in the gene for plakophilin I which caused an autosomal recessive skin fragility-ectodermal dysplasia syndrome with skin, hair and nail defects [5].

High impact information on PKP1

• Mutations in the plakophilin 1 gene result in ectodermal dysplasia/skin fragility syndrome [6].
• The molecular findings and clinical observations in this patient attest to the dual importance of plakophilin 1 in both cutaneous cell-call adhesion and epidermal morphogenesis [6].
• The affected individual has a complete absence of immunostaining for plakophilin 1 in the skin and is a compound heterozygote for autosomal-recessively inherited premature termination codons of translation on both alleles of the plakophilin 1 gene (PKP1) [6].
• This effect was mediated by plakophilin 1's head domain, which interacted with desmoglein 1, desmoplakin, and keratins in the yeast two-hybrid system [7].
• The function of plakophilin 1 in desmosome assembly and actin filament organization [7].

Biological context of PKP1

• The absence of the mutant mRNA and plakophilin 1 protein in the proband's skin may result from the mechanism of nonsense-mediated mRNA decay induced by premature stop codons in PKP1 transcripts due to the two splice site mutations [8].
• Using fluorescence in situ hybridization, we have localized the human genes for the three known plakophilins to the chromosomes 1q32 (PKP1), 12p11 (PKP2) and 11p15 (PKP3) [9].
• Plakophilin 1, a member of the armadillo multigene family, is a protein with dual localization in the nucleus and in desmosomes [7].
• Thus, both the patients and unaffected carrier showed reductions in the LSB desmosome size and number; despite only PkP1 null patients exhibiting any phenotype [10].
• The plakophilin 1 (PKP1) and plakoglobin (JUP) genes map to human chromosomes 1q and 17, respectively [11].

Anatomical context of PKP1

• We have determined the crystal structure of the arm repeat domain from plakophilin-1 (PKP1), a member of the p120ctn subfamily that is found in desmosomes [12].
• In addition, plakophilin 2 is less efficient than plakophilin 1 in localizing to the nucleus and enhancing the recruitment of excess desmoplakin to cell borders in transiently transfected COS cells [13].
• When overexpressed in HaCaT keratinocytes, plakophilin 1 localized to the nucleus and to desmosomes, and dramatically enhanced the recruitment of desmosomal proteins to the plasma membrane [7].
• Our results demonstrate that plakophilin 1 contains two functionally distinct domains: the head domain, which could play a role in organizing the desmosomal plaque in suprabasal cells, and the armadillo repeat domain, which might be involved in regulating the dynamics of the actin cytoskeleton [7].
• These results suggest that p120ctn/plakophilin family proteins interact with intercellular junction binding partners to differentially modulate the adhesive and migratory behavior of epithelial cells [14].

Associations of PKP1 with chemical compounds

• Our results suggest that, in the Triton soluble pool, PKP1 interferes with binding of plakoglobin to full length DP when these proteins are co-expressed [15].
• Treatments such as protease digestion and chemical modification with acetic anhydride, succinic anhydride, or diazobenzenesulfonic acid destroyed the TF1-binding activity, which was caused by band 6 protein [16].
• In resealed ghosts, Band 6 labeling was decreased by D-glucose, reflecting inhibition of carrier-mediated uptake of the agent [17].
• Two major polypeptides remained associated with Band 3 under these conditions; however one (Band 6) could be dissociated at an ionic strength of 0.15 and the other (Band 4.2) by treatment with p-chloromercuribenzoate [18].
• Band 6 photolabeling in leaky ghosts by GlcNAs was: saturable, due mostly to the aryl azide moiety, inhibited by agents with known affinity for the enzyme including sulfhydryl reagents and the enzyme substrate glyceraldehyde-3-phosphate, and not inhibited by the free-radical scavenger p-aminobenzoic acid [17].

Physical interactions of PKP1

• Plakophilin 1 interferes with plakoglobin binding to desmoplakin, yet together with plakoglobin promotes clustering of desmosomal plaque complexes at cell-cell borders [15].
• In 2000, we developed and applied a single cell nested polymerase chain reaction protocol to test one couple for compound heterozygous plakophilin 1 gene mutations by preimplantation genetic diagnosis (PGD) [19].

Other interactions of PKP1

• Interestingly, like DP, PG and PP1 associate with epidermal keratins, although PG is considerably weaker in its ability to do so [20].
• Plakophilin 1 and 2 (PKP1, PKP2) are members of the arm-repeat protein family [21].
• PKP1 and PKP3 immunoreactivity was inversely correlated with tumor histological grade and was observed only in tumors that did not metastasize [1].
• While there was no appreciable difference between ADO rates between the two lysis buffers for the LAMA3 PCR product (25% vs 26%), there were significant differences in ADO rates between ALB and PK for the CFTR PCR product (0% vs 23%) and the PKP1 PCR product (8% vs 56%) [22].
• To address this issue, PCR amplification of three genes (CFTR, LAMA3 and PKP1) at different chromosomal loci was investigated [22].

Analytical, diagnostic and therapeutic context of PKP1

• Therefore we have used circular dichroism spectroscopy, limited proteolysis, analytical ultracentrifugation, electron microscopy and dynamic light scattering to establish the physical properties of recombinant PKP1 depending on the presence or absence of zinc [23].
• In surface plasmon resonance detection experiments, we noticed that PKP1 specifically bound zinc but not calcium or magnesium [23].
• In contrast, PKP1, reconstituted without zinc, contained no significant amount of zinc, sedimented with 4.6S, and was present in monomeric form as determined by sedimentation equilibrium centrifugation [23].
• Preimplantation genetic diagnosis of compound heterozygous mutations leading to ablation of plakophilin-1 (PKP1) and resulting in skin fragility ectodermal dysplasia syndrome: a case report [24].
• In this study, we used a cell culture system (A431DE cells) that expresses all of the proteins necessary to assemble a desmosome, except plakophilin-1 [25].

References