Plakoglobin

Plakoglobin, also known as junction plakoglobin or gamma-catenin, is a is_associated_with::protein that in humans is encoded by the JUP is_associated_with::gene. Plakoglobin is a member of the is_associated_with::catenin protein family and homologous to β-catenin. Plakoglobin is a cytoplasmic component of is_associated_with::desmosomes and is_associated_with::adherens junctions structures located within is_associated_with::intercalated discs of is_associated_with::cardiac muscle that function to anchor is_associated_with::sarcomeres and join adjacent cells in is_associated_with::cardiac muscle. Mutations in plakoglobin are associated with is_associated_with::arrhythmogenic right ventricular dysplasia and is_associated_with::Pemphigus vulgaris.

Structure
Human plakoglobin is 81.7 kDa in molecular weight and 745 amino acids long. The JUP gene contains 13 exons spanning 17 kb on chromosome 17q21. Plakoglobin is a member of the is_associated_with::catenin family, since it contains a distinct repeating amino acid motif called the is_associated_with::armadillo repeat. Plakoglobin is highly homologous to β-catenin; both have 12 is_associated_with::armadillo repeats as well as N-terminal and C-terminal globular domains of unknown structure. Plakoglobin was originally identified as a component of is_associated_with::desmosomes, where it can bind to the is_associated_with::cadherin family member desmoglein I. Plakoglobin also associates with classical cadherins such as is_associated_with::E-cadherin; in that context, it was called gamma-is_associated_with::catenin. Plakoglobin forms distinct complexes with is_associated_with::cadherins and desmosomal cadherins.

Function
Plakoglobin is a major cytoplasmic component of both is_associated_with::desmosomes and is_associated_with::adherens junctions, and is the only known constituent common to submembranous plaques in both of these structures, which are located at the intercalated disc (ICD) of cardiomyocytes. Plakoglobin links is_associated_with::cadherins to the is_associated_with::actin is_associated_with::cytoskeleton. Plakoglobin binds to conserved regions of desmoglein and desmocollin at is_associated_with::intracellular is_associated_with::catenin-binding sites to assemble is_associated_with::desmosomes.

Plakoglobin is essential for normal development of is_associated_with::intercalated discs and stability of is_associated_with::cardiac muscle. Transgenic mice homozygous for a null mutation of the JUP gene die around embryonic day 12 from substantial defects in is_associated_with::adherens junctions and a lack of functional desmosomes in the heart. Further studies showed that is_associated_with::cardiac fibers obtained from JUP-null embryonic mice had decreased passive compliance albeit normal attachment of is_associated_with::sarcomeres to is_associated_with::adherens junctions.

In additional studies, an inducible is_associated_with::cardiac-specific plakoglobin knockout mice were generated. Transgenic mice displayed a similar phenotype as is_associated_with::arrhythmogenic right ventricular cardiomyopathy patients, with loss of is_associated_with::cardiomyocytes, is_associated_with::fibrosis and cardiac dysfunction, as well as alterations in is_associated_with::desmosome protein content and is_associated_with::gap junction remodeling. Hearts also exhibited increases in β-catenin signaling. Further investigations on the role of β-catenin and plakoglobin in the heart generated a double knockout of these two proteins. Mice exhibited is_associated_with::cardiomyopathy, is_associated_with::fibrosis, conduction abnormalities and is_associated_with::sudden cardiac death, presumably via spontaneous lethal ventricular is_associated_with::arrhythmias. Mice also showed a decrease in is_associated_with::gap junction structures at is_associated_with::intercalated discs.

Intracellular plakoglobin expression s controlled by is_associated_with::Wnt signaling and ubiquitin-is_associated_with::proteasome-dependent degradation. is_associated_with::Phosphorylation of N-terminal is_associated_with::Serines by a “destruction complex” composed of glycogen synthase kinase 3β (GSK3β) and scaffold proteins is_associated_with::adenomatous polyposis coli (APC) and axin targets plakoglobin for degradation. [31–33]. The phosphorylated motif is recognized by β-TrCP, a ubiquitin ligase that targets plakoglobin 26S proteasome-dependent degradation. Plakoglobin is also O-glycosylated near its N-terminal destruction box.

Clinical significance
Mutation of the JUP gene encoding plakoglobin has been implicated as one of the causes of the is_associated_with::cardiomyopathy known as is_associated_with::arrhythmogenic right ventricular dysplasia (ARVD) or is_associated_with::arrhythmogenic right ventricular cardiomyopathy; mutations in JUP specifically causes an is_associated_with::autosomal recessive form referred to as is_associated_with::Naxos disease. This form of was first identified in a small cluster of families on the Greek island of Naxos. The phenotype of the is_associated_with::Naxos disease variant of ARVD is unique in that it involves the hair and skin as well as the right is_associated_with::ventricle. Affected individuals have kinky, is_associated_with::wooly hair; there is also palmar and plantar is_associated_with::erythema at birth that progresses to is_associated_with::keratosis as the palms and soles of the feet are used in crawling and walking. These findings co-segregate 100% with the development of ARVD by early adolescence.

It has become clear that ARVD/ARVC is a disease of the is_associated_with::cardiac muscle is_associated_with::desmosome; advances in molecular genetics have illuminated this notion.

Studies investigating the role of plakoglobin in disease pathology have found that suppression of desmoplakin expresion by is_associated_with::siRNA led to the nuclear localization of plakoglobin, resulting in a reduction in is_associated_with::Wnt signaling via Tcf/Lef1 and ensued pathogenesis of ARVC. Specifically, adipogenic factor expression was induced and cardiac progenitor cells at the epicardium were differentiated to adipocytes.

Non-invasive is_associated_with::cardiac screening identified T-wave inversion, abnormalities in right ventricular wall motion, and frequent ventricular extrasystoles as sensitive and specific markers of a JUP mutation. Additional studies have shown that immunohistochemical analysis of is_associated_with::cardiac muscle desmosomal proteins is also a sensitive and specific diagnostic text for ARVD/ARVC.

Abnormal distribution of plakoglobin due to mutations in genes encoding for is_associated_with::Desmoglein 1 and 3 have also been implicated in is_associated_with::Pemphigus vulgaris.

Interactions
Plakoglobin has been shown to interact with:


 * APC,
 * CTNNA1,
 * CTNNB1,
 * CDH1,
 * is_associated_with::CDH2,
 * CDH3,
 * CDH5,
 * DSG2,
 * DSP,
 * is_associated_with::MUC1,
 * is_associated_with::PKP2,
 * PTPkappa (is_associated_with::PTPRK),
 * PTPrho (is_associated_with::PTPRT), and
 * is_associated_with::PDLIM3.