JUP

What is JUP Protein?

JUP gene (junction plakoglobin) is a protein coding gene which situated on the long arm of chromosome 17 at locus 17q21. This gene encodes a major cytoplasmic protein which is the only known constituent common to submembranous plaques of both desmosomes and intermediate junctions. This protein forms distinct complexes with cadherins and desmosomal cadherins and is a member of the catenin family since it contains a distinct repeating amino acid motif called the armadillo repeat. Mutation in this gene has been associated with Naxos disease. The JUP protein is consisted of 745 amino acids and JUP molecular weight is approximately 81.7 kDa.

What is the Function of JUP Protein?

The JUP protein, also known as Plakoglobin, is a protein involved in cell junctions, mainly involved in adhesion junctions and the structural composition of desmosomes. It belongs to a member of the Catenin family and contains a characteristic repeating amino acid sequence called the armadillo repeat. The functional diversity of JUP proteins enables them to have different effects in different biological processes. For example, in terms of cell adhesion, JUP contributes to intercellular adhesion and affects the structural stability of tissues. The expression of JUP is particularly important in heart and skin cells, where it is involved in forming cellular connections between the heart and skin. In addition, JUP is associated with the Wnt signaling pathway, which plays a key role in controlling the activity of specific genes and interactions between cells.

JUP Related Signaling Pathway

In gastric cancer, the interaction of JUP protein with EGFR (epidermal growth factor receptor) is thought to regulate the AKT/GSK3β/β-catenin signaling pathway, influencing cancer cell invasion and metastasis. JUP, as a homologous protein of β-catenin, may play a role in the Wnt signaling pathway. For example, the JUP protein interacts with β-catenin and TCF4 to synergistically promote TCF4 transcriptional activity and affect the expression of downstream genes such as MMP7, which may be related to the invasive ability of cancer cells. In bladder cancer, DHT (dihydrotestosterone) promotes the proliferation and invasion of bladder cancer cells through EPPK1-mediated MAPK/JUP signaling pathway. In colorectal cancer, binding of ICAT (a suppressor of the Wnt signaling pathway) to the JUP protein activates the NF-κB signaling pathway, which may promote metastasis of colorectal cancer cells.

JUP Related Diseases

The JUP protein has been implicated in a variety of diseases, especially those related to skin, heart, and tumors. JUP may play a dual role in tumor development. For example, in gastric cancer, the expression level and cell location of JUP are closely related to the malignancy and prognosis of the tumor. In addition, JUP has been associated with the prognosis of a variety of cancers, such as having a positive role as a prognostic marker in kidney cancer. Mutations in the JUP gene have also been linked to Naxos disease, a genetic disorder involving the heart and skin. In urinary tract tumors, JUP inhibits tumor occurrence and metastasis through a variety of mechanisms. In colorectal cancer, the increased expression of JUP may be related to tumor progression. In addition, JUP also plays a role in heart failure induced by hypertrophy of the heart, and Mycn improves heart failure through the USP2/JUP/Akt/ beta-catenin cascade. In desmosomal diseases, mutations in JUP can lead to serious skin problems and heart problems. In neuroblastoma, JUP inhibits the proliferation and invasion of tumor cells by inhibiting the Wnt/β-catenin signaling pathway.

Fig1. Model of the role of PG in prostate cancer adhesion and motility. (Carrie A Franzen, 2012)

Bioapplications of JUP

JUP protein has many potential applications in medical research and clinical therapy. First of all, as an important component of intercellular connectivity, the change of JUP expression level is closely related to the radiotherapy resistance, proliferation and invasion ability of tumors. For example, in cervical cancer, low expression of JUP is associated with radiation resistance, and reduced expression of JUP is associated with enhanced migration of tumor cells. In addition, JUP can reduce Wnt/β-catenin signaling pathway activity by interacting with β-catenin and inhibiting its nuclear translocation, thereby inhibiting the proliferation and invasion of neuroblastoma. In gastric cancer, the function of JUP is related to its cell location during tumor development, and the loss of membrane and/or cytoplasmic JUP is associated with malignancy and poor prognosis. These findings suggest that JUP may serve as a potential target for tumor therapy, especially in terms of radiation sensitization and signaling pathway regulation.

Case Study 1: Stephanie A Matthes, 2015

Fibroblast activation in IPF is associated with Wnt/β-catenin signaling, but little is known about the role of the β-catenin-homologous desmosomal protein, plakoglobin (PG), in IPF. The objective of this study was to assess the functional role of PG in human lung fibroblasts in IPF. Human lung fibroblasts from normal or IPF patients were transfected with siRNA targeting PG and used to assess cellular adhesion to a fibronectin substrate, apoptosis and proliferation. The results showed that IPF lung fibroblasts expressed less PG protein than control fibroblasts, but that characteristic fibroblast phenotypes (adhesion, proliferation, and apoptosis) were not controlled by PG expression. Consistent with this, normal fibroblasts in which PG was silenced displayed no change in functional phenotype.

Fig1. Normal (white) or IPF (black) whole lung lysates were assessed for PG protein expression by western blot.

Fig2. Treatment of lung fibroblasts with siRNA-PG dramatically reduces cellular PG protein expression as shown in a western blot.

Case Study 2: Volker Spindler, 2014

Plakoglobin (Pg) and desmoplakin (DP) are adapter proteins within the desmosome, providing a mechanical link between desmosomal cadherins as transmembrane adhesion molecules and the intermediate filament cytoskeleton. As in the severe skin blistering disease pemphigus, autoantibodies against desmosomal adhesion molecules induce loss of keratinocyte cohesion at least in part via p38 mitogen-activated protein kinase (p38MAPK) activation and depletion of desmosomal components, researchers evaluated the roles of Pg and DP in the p38MAPK-dependent loss of cell adhesion. Silencing of either Pg or DP reduced cohesion of cultured human keratinocytes in dissociation assays. However, Pg but not DP silencing caused activation of p38MAPK-dependent keratin filament collapse and cell dissociation. Interestingly, extranuclear but not nuclear Pg rescued loss of cell adhesion and keratin retraction. In line with this, Pg regulated the levels of the desmosomal adhesion molecule desmoglein 3 and tethered p38MAPK to desmosomal complexes.

Fig3. Immunoblots of whole-cell lysates demonstrate that AK23 and PV-IgG reduce Pg and desmoglein 3 (Dsg3) protein content, but not that of DP.

Fig4. Expression of Pg-WT or NES-Pg reduced the amount of active p38MAPK as detected by immunoblots of whole-cell lysates.

JUP has several biochemical functions, for example, alpha-catenin binding,cadherin binding,cell adhesion molecule binding. Some of the functions are cooperated with other proteins, some of the functions could acted by JUP itself. We selected most functions JUP had, and list some proteins which have the same functions with JUP. You can find most of the proteins on our site.

JUP has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with JUP here. Most of them are supplied by our site. Hope this information will be useful for your research of JUP.

APC;PSEN1;WDYHV1;PECAM1;TCF7L2