EZR

Official Full Name

ezrin

Organism

Homo sapiens

GeneID

7430

Background

The cytoplasmic peripheral membrane protein encoded by this gene functions as a protein-tyrosine kinase substrate in microvilli. As a member of the ERM protein family, this protein serves as an intermediate between the plasma membrane and the actin cytoskeleton. This protein plays a key role in cell surface structure adhesion, migration and organization, and it has been implicated in various human cancers. A pseudogene located on chromosome 3 has been identified for this gene. Alternatively spliced variants have also been described for this gene. [provided by RefSeq, Jul 2008]

Synonyms

CVL; CVIL; VIL2; HEL-S-105;

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Detailed Information

The Ezrin (Ezr) protein is a member of the ERM (Ezrin; Radixin; Moesin) protein family. As a substrate for tyrosine kinases, Ezrin proteins act as a bridge between cell membrane proteins and actin skeletons. In recent years, a large number of studies have shown that Ezrin protein is widely involved in breast cancer cell proliferation, apoptosis, adhesion, invasion and metastasis, and regulation of neovascularization.

Ezrin protein is a member of the ERM protein family, a connexin between membrane proteins and actin skeleton, involved in cell morphology maintenance, movement, adhesion, signal transduction and other processes. The gene encoding Ezrin protein VIL2 (Villin2) is located on the chromosome 6q25-6q26 and contains 13 exons, which are 24Kb in length. The Ezrin protein consists of 585 amino acid residues with a relative molecular mass of 81 kD.

The Ezrin protein consists mainly of three domains: a highly conserved globular amino-terminal FERM domain, an intermediate elongated α helix region and a carboxy-terminal domain. FERM domain comprises amino-terminal 296 amino acids, three independent folding domains i.e. α helix of ubiquitin-like fold near the amino terminus of the sequence, which is referred to as F1. The F2 fragment resembles a fatty acyl-CoA binding protein, and F3 is similar to the pleckstrin protein homology domain (PH)/phosphotyrosine binding domain (PTB).

This domain can bind directly or indirectly to protein molecules located on the membrane such as CD44, ICAM-1, ICAM-2, NHE1 (Na+/H+ exchanger), E-Cadherin, integrins and the like. The carboxy terminus is a positively charged actin backbone binding region. The 34-amino acid residue at the tail end contains the binding site of F-actin, thereby transmitting the membrane signal to the cytoplasm. In the middle is the α-helix connecting the FERM domain and the carboxy terminus, and its specific function in the entire Ezrin protein molecule remains to be further studied.

Distribution of Ezrin Protein

The expression level of Ezrin protein is tissue-specific and is highly expressed in tissues such as the intestine, stomach, lung, and kidney, while the heart, brain, and muscle are expressed at low levels. Moreover, the subcellular localization of the cells also has certain specificity. It is worth noting that the subcellular localization of Ezrin protein is not fixed and can be affected by intracellular and extracellular stimulation signals. Ezrin protein is generally expressed in epidermal cells and mesothelial cells. It is mainly distributed in the apical structure of the actin-rich plasma membrane and accumulates in the inner side of the plasma membrane, such as microvilli, membrane folds, filopodia, and intercellular junctions.

Ezr Figure 1. The regulation of bile secretion by ezrin in cholangiocytes.( Fouassier, et al. 2015)

Fouassier et al. showed that ERM proteins are expressed in hepatocytes and biliary cells. The Ezrin protein localizes to the apical actin-rich region of biliary cells, where it contributes to the organization of multiprotein complexes. Ezrin regulates membrane localization and activation of CFTR. The FERM domain of Ezrin protein indirectly anchors CFTR via the PDZ protein EBP50, while the C-terminal domain interacts with F-actin to promote stabilization of the channel on the membrane. Ezrin can bind to other proteins such as PKA to aid in the regulation of CFTR.

Using the Ezrin protein antibody to detect its nuclear localization, it was found that the full-length endogenous Ezrin protein was localized to the nucleus in a density-dependent manner, that is, the cells in the confluent state were mostly at rest and had no migration ability. The nuclear expression of Ezrin protein is at baseline; whereas in the subconfluent state of migration, the nuclear localization of Ezrin protein is significantly increased. This suggests that the nuclear distribution of the Ezrin protein may primarily regulate cell movement rather than proliferation. The nuclear localization properties of Ezrin proteins may be another potential mechanism for cell motility regulation.

Ezrin and Breast Cancer

In human breast cancer cells, high overexpression of p-T567-Ezrin protein is positively correlated with the invasive growth of cancer cells and overexpression of HER2. By comparing the expression of Ezrin protein in normal breast tissue, benign and malignant breast cancer tissues, Gschwantler-Kaulich et al. found no significant difference in Ezrin protein expression between normal and benign breast cancer tissues. It is significantly increased in malignant breast cancer tissues and is reflected in both mRNA and protein levels.

The study found that Ezrin proteins maintain submembrane localization in non-invasive, ER-positive, and non-tumorigenic cell lines. In invasive breast cancer cells, Ezrin protein is localized in the cell structure region such as membrane fold region and filopodia, and exhibits scattered cytoplasmic staining. It was also found that the cytoplasmic localization of Ezrin protein is closely related to the developmental grade, proliferation level and yin and yang status of sex hormone receptors in breast cancer. Therefore, the transfer of Ezrin protein from the membrane structural region to the cytoplasm may be an independent marker of the invasion potential of breast cancer.

The expression level of Ezrin protein can affect the expression of E-cadherin and membrane localization ability. Ezrin protein is expressed at a low level, and E-cadherin is mainly localized to the membrane of breast cancer cells. When Ezrin protein is overexpressed, the distribution of E-cadherin in the cytoplasm is significantly higher than that of normal cells and benign tumor cells. This is closely related to the lymphatic metastasis ability of breast cancer and the survival prognosis of patients. The generation of primary tumor neovascularization can provide a path for nutrient and migration invasion and distant metastasis of breast cancer cells. Ghaffari et al. showed that high expression of Ezrin and c-Src in breast cancer is closely related to lymphatic invasion. C-Src kinase phosphorylates Ezrin protein Y477 to induce the transformation of breast cancer AC2M2 cell line into invading cell type. Ezrin protein may be involved in the regulation of angiogenesis, and the specific mechanism still needs further study.

References:

Viswanatha, R., Wayt, J., Ohouo, P. Y., Smolka, M. B., & Bretscher, A. (2013). Interactome analysis reveals ezrin can adopt multiple conformational states. Journal of Biological Chemistry, 288(49), 35437-35451.
Fouassier, L., & Fiorotto, R. (2015). Ezrin finds its groove in cholangiocytes. Hepatology, 61(5), 1467-1470.
Antelmi, E., Cardone, R. A., Greco, M. R., Rubino, R., Sole, F. D., & Martino, N. A., et al. (2013). ß1 integrin binding phosphorylates ezrin at t567 to activate a lipid raft signalsome driving invadopodia activity and invasion. Plos One, 8(9), e75113.
Gschwantler-Kaulich, D., Natter, C., Steurer, S., Walter, I., Thomas, A., & Salama, M., et al. (2013). Increase in ezrin expression from benign to malignant breast tumours. Cellular Oncology, 36(6), 485-491.
Jais, M. H., Md Zin, R. R., Muhd Hanapi, N. A., & Md Ali, S. A. (2015). Ezrin is significantly overexpressed in luminal a, luminal b, and her2 subtype breast cancer. Applied Immunohistochemistry & Molecular Morphology Aimm, 25(1), 44.
Yu Z, Sun M, Jin F, Xiao Q, He M, & Wu H, et al. (2015). Combined expression of ezrin and e-cadherin is associated with lymph node metastasis and poor prognosis in breast cancer. Oncology Reports, 34(1), 165.
Ghaffari, A., Hoskin, V., Szeto, A., Hum, M., Liaghati, N., & Nakatsu, K., et al. (2015). A novel role for ezrin in breast cancer angio/lymphangiogenesis. Breast Cancer Research, 17(1), 1-1.

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