CDH4

Fig1. Parallel heterodimers and homophilic interactions form between cadherins in R-/N-cadherin coexpressing cells. (W S Shan, 2000)

What is CDH4 protein?

CDH4 (cadherin 4) gene is a protein coding gene which situated on the long arm of chromosome 20 at locus 20q13. This gene is a classical cadherin from the cadherin superfamily. The encoded protein is a calcium-dependent cell-cell adhesion glycoprotein comprised of five extracellular cadherin repeats, a transmembrane region and a highly conserved cytoplasmic tail. This cadherin is thought to play an important role during brain segmentation and neuronal outgrowth. In addition, a role in kidney and muscle development is indicated. The CDH4 protein is consisted of 916 amino acids and its molecular mass is approximately 100.3 kDa.

What is the function of CDH4 protein?

CDH4 is an adhesion protein expressed at the junctions between cells and belongs to the cadherin family. It helps cells establish and maintain tight connections by binding to Cadherin 4 or other types of Cadherins on the surface of other cells. It can participate in the formation and maintenance of specific tissue morphology, and its expression patterns in various tissues play a key role in determining cell fate and tissue differentiation.

CDH4 Related Signaling Pathway

CDH4 binds to Cadherin molecules on other cells through its extracellular domain, thereby mediating adhesion between homogeneic and heterogeneic cells. This interaction can activate a variety of downstream signaling events, including regulating the organization of the cytoskeleton, influencing cell morphology, and controlling cell migration and proliferation. In the cell, the cytoplasmic tail of Cadherin 4 can interact with a variety of proteins, such as β-catenin, α-catenin, and other signaling molecules, and then connect to the actin cytoskeleton to participate in signal transduction. Cadherin 4 May also be involved in certain signaling pathways, such as the classic Wnt/ beta-catenin pathway, which plays a crucial role in cell fate determination and tissue regeneration.

CDH4 Related Diseases

Hereditary Diffuse Gastric Cancer (HDGC): Due to the mutation of CDH4 gene, the adhesion between intestinal epithelial cells is weakened, which increases the risk of cancer, especially gastric cancer. More types of cancer were also associated, including lung adenocarcinoma, liver cancer, and stomach cancer.

Bioapplications of CDH4

In recent years, researchers have developed antibody drugs that target CDH4 that block CDH4 interactions between tumor cells and surrounding normal cells, thereby inhibiting tumor invasion and metastasis. In addition, CDH4 has been used as a molecular marker for certain tumor subtypes, enabling individualized therapy.

Case study 1: Jian Xie, 2023

The cadherin-4 gene (CDH4), a member of the cadherin family genes, encodes R-cadherin (R-cad); however, the function of this gene in different types of cancer remains controversial. The function of CDH4 in OSCC (oral squamous cell carcinoma) is unknown.

The related cell function assay detected that CDH4 promotes the ability of cell proliferation, migration, self-renewal and invasion. Cell staining experiment confirmed that the change of CDH4 expression would change the cell mortality. The western blot of GPX4 (glutathione-dependent peroxidase-4), GSH (reduced glutathione) test assay and MDA(Malondialdehyde) test assay show that the expression of CDH4 may resist the sensitivity of ferropotosis in OSCC. High expression of CDH4 effectively promotes the proliferation, mobility of OSCC cells and reduce the sensitivity of OSCC cells to ferroptosis. CDH4 is positively correlated with EMT pathway genes, negatively correlated with fatty acid metabolism pathway genes and peroxisome pathway genes, and positively correlated with ferroptosis suppressor genes in OSCC.

Fig1. CDH4 expression was effectively reduced by siRNAs as measured by western blot in HN30 cells.

Fig2. The western blot experiment showed the expression of GPX4 in the CDH4 down-regulation experiment.

Case study 2: Emhonta Johnson, 2004

Classical cadherins are the transmembrane proteins of the adherens junction and mediate cell-cell adhesion via homotypic interactions in the extracellular space. In addition, they mediate connections to the cytoskeleton by means of their association with catenins. Decreased cadherin-mediated adhesion has been implicated as an important component of tumorigenesis. Cadherin switching is central to the epithelial to mesenchymal transitions that drive normal developmental processes. Cadherin switching has also been implicated in tumorigenesis, particularly in metastasis. Recently, cadherins have been shown to be engaged in cellular activities other than adhesion, including motility, invasion, and signaling. In this study, the researchers show that inappropriate expression of R-cadherin in tumor cells results in decreased expression of endogenous cadherins (cadherin switching) and sustained signaling through Rho GTPases. In addition, we show that R-cadherin induces cell motility when expressed in epithelial cells and that this increased motility is dependent upon Rho GTPase activity.

Fig3. Immunoblots. 40 μg of total protein were resolved by SDS-7% PAGE, transferred to nitrocellulose, and immunoblotted with antibodies against E-cadherin, P-cadherin, or R-cadherin(myc).

Fig4. R-cadherin modulates Rho GTPase activity. Rho GTPase pull down assays were used to evaluate GTP binding of Rac1, Cdc42, and RhoA.

CDH4 has several biochemical functions, for example, calcium ion binding. Some of the functions are cooperated with other proteins, some of the functions could acted by CDH4 itself. We selected most functions CDH4 had, and list some proteins which have the same functions with CDH4. You can find most of the proteins on our site.

CDH4 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 CDH4 here. Most of them are supplied by our site. Hope this information will be useful for your research of CDH4.

Dlg4