Disease relevance of PKP2

• Thus consistent PKP2 immunostaining has been observed in all 18 cases of adenocarcinomas tested, but more variable and heterogeneous staining has been noted in squamous cell carcinomas, depending on the specific tumor type [1].
• The results suggest that mAbs to PKP2 may serve as markers for the identification and characterization of carcinomas derived from--or corresponding to--simple or complex epithelia [1].
• Inducibility of ventricular arrhythmias on an electrophysiology study, diffuse nature of right ventricular disease, and presence of prior spontaneous ventricular tachycardia were identified as predictors of implanted cardioverter/defibrillator (ICD) intervention only among patients without a PKP2 mutation (P<0.05) [2].
• AIMS: To evaluate clinical disease expression, non-invasive diagnosis, and prognosis in families with dominant vs. recessive arrhythmogenic right ventricular cardiomyopathy (ARVC) due to mutations in related desmosomal proteins plakophilin-2 (PKP2) and plakoglobin (JUP), respectively [3].
• METHODS: We sequenced PKP2 from genomic DNA isolated from peripheral blood lymphocytes in a female proband who presented with cardiac arrest and in her four first-degree relatives [4].

High impact information on PKP2

• In 32 of 120 unrelated individuals with ARVC, we identified heterozygous mutations in PKP2, which encodes plakophilin-2, an essential armadillo-repeat protein of the cardiac desmosome [5].
• Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy [5].
• Functional analysis of C-TAK1 substrate binding and identification of PKP2 as a new C-TAK1 substrate [6].
• However, plakophilin 2 has also been localized in the desmosomes of certain but not all stratified epithelia where it coexists with plakophilin 1 [7].
• We also show that plakophilin 2 is present in the pol III holoenzyme, but not the core complex, and that it binds specifically to RPC155 in vitro [8].

Biological context of PKP2

• 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].
• METHODS AND RESULTS: To establish the prevalence and character of PKP2 mutations and to study potential differences in the associated phenotype, we evaluated 96 index patients, including 56 who fulfilled the published task force criteria [10].
• Protein binding and functional characterization of plakophilin 2. Evidence for its diverse roles in desmosomes and beta -catenin signaling [11].
• Gender may have an influence on penetrance of PKP2 mutations, with male mutation carriers more likely to develop specific phenotypic manifestations of this disease [12].
• After the characterisation of mutations in the plakophilin-2 gene, molecular genetics is going to become an important diagnostic tool [13].

Anatomical context of PKP2

• These mAbs detect PKP2 in characteristic desmosomes of most normal cells, including simple and stratified epithelia as well as non-epithelial tissues such as myocardium and lymph node follicles [1].
• 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 [11].

Other interactions of PKP2

• Plakophilin 1 and 2 (PKP1, PKP2) are members of the arm-repeat protein family [14].
• METHODS AND RESULTS: In a series of 80 unrelated ARVC probands, 26 carried a mutation in DSP (16%), PKP2 (14%), and transforming growth factor-beta3 (2.5%) genes; the remaining 54 were screened for DSG2 mutations by denaturing high-performance liquid chromatography and direct sequencing [15].
• Pathogenic D gene mutations were identified in 10 (48%): desmoglein-2 in four, desmoplakin in three and plakophilin-2 in three [16].
• METHODS AND RESULTS: One hundred and eighty-seven individuals belonging to ARVC families, four with dominant PKP2 mutations and 12 with recessive JUP mutation underwent serial non-invasive cardiac assessment [3].
• Recessive arrhythmogenic right ventricular dysplasia due to novel cryptic splice mutation in PKP2 [17].

Analytical, diagnostic and therapeutic context of PKP2

• Plakophilin 2 (PKP2) is a widespread protein which shows a remarkable dual location: On the one hand, it appears as a constitutive karyoplasmic protein and on the other it is a desmosomal plaque component of most, probably all, desmosome-possessing tissues and cell culture lines [1].
• Using antibodies and recombinant DNA techniques, we have identified plakophilin 2, a novel desmosomal plaque protein of M(r) 100,000 (estimated from SDS-PAGE), which is a member of the arm-repeat family of proteins and can occur in two splice forms (2a and 2b) because of the insertion of a 44 amino acid (aa)-encoding exon [7].
• To better understand the cellular functions of plakophilin 2, we have examined its protein interactions with other junctional molecules using co-immunoprecipitation and yeast two-hybrid assays [11].
• Male PKP2 mutation carriers were more likely to have structural and conduction abnormalities as determined by imaging studies, signal-averaged electrocardiography, and 24-h ambulatory electrocardiography (p < 0.05) [12].

References