EMPs are hydrophobic proteins of approximately 160 amino acid residues with four predicted transmembrane domains, two extracellular domains, and small intracellular regions (Figure 1). The molecular structures of EMP2 and EMP3 share features such as protein kinase C phosphorylation sites, but EMP1 lacks these sites. EMP1 and EMP2 contain casein kinase-2 phosphorylation sites. All of the EMPs have N-glycosylation sites. The amino acid sequence of human PMP22 is 35%, 39%, and 41% identical to those of human EMP1, EMP2, and EMP3, respectively. The amino acid sequences of the predicted transmembrane domains are highly conserved among the EMP family members.

Figure 1. Structural difference between EMPs, and signal transduction molecules of which expression and/or activation are affected by EMPs in the regulation of cancer invasion and metastasis. The number and position of N-glycosylation and the kinase-mediated phosphorylation are different between EMPs. Numerous signaling molecules and cell surface proteins are associated with the role of EMPs. They mediate the EMP-induced cellular functions, such as proliferation and migration, that regulate the invasiveness of cancer cells and subsequent metastatic events. Red arrows: increase or activation of the molecules or phenomena; blue arrows: decrease or inactivation of the molecules or phenomena.

Analysis of the HPA, GTEx, and FANTOM5 datasets shows that EMP1 mRNA levels are high in the esophagus, followed by adipose tissue, and the gallbladder. Further, the levels of EMP1 protein are highest in the stomach, but low in other tissues.

EMP1 is expressed during the development of the central and peripheral nervous systems, suggesting its association with neurogenesis. Moreover, EMP1 is involved in the regulation of the cell cycle, cell-to-cell interactions, and cell death. During the growth of fibroblasts and Schwann cells, the expression of EMP1 is inversely regulated by PMP22, and EMP1 is a novel tight junction protein of the blood-brain barrier.

EMP2 is most commonly expressed in the lung, skin, and esophagus and is least likely to be expressed in the pancreas and brain according to the Human Protein Atlas. EMP2 is expressed in multiple structures of the eye, such as the cornea, ciliary body, and the epithelium of retina. The transcript level of EMP2 is elevated in the fetal lung and kidney, but not in the adult thymus and peripheral leukocytes.

EMP2 localizes within lipid raft domains and is likely to modulate the plasma membrane trafficking activities of integrins and major histocompatibility complex class 1 proteins. EMP2 regulates the physiological function of several integrins during blastocyst implantation, cell division, adhesion, and migration. In a retinal epithelial cell line, EMP2 induces intracellular collagen gel contraction through the activation of focal adhesion kinase (FAK) at two phosphorylation sites Tyr576 and Tyr577. EMP2 and the activation of FAK are closely associated with integrin β1 subunits. The enhancement of cellular adhesion to collagens types I and IV, the increase in expression of α-smooth muscle actin, and the activation of F-actin, particularly at the cell periphery, are detected in retinal epithelial cells that overexpress EMP2. These findings indicate that EMP2 may function in the reorganization of the actin cytoskeleton and enhance cellular contractility and adhesion.

EMP3 is expressed in numerous organs, as indicated in the Human Protein Atlas. Unlike EMP2, the levels of EMP3 mRNA are high in the adult peripheral leukocytes and relatively strong in the fetal lungs, liver, and kidneys. However, lower levels are expressed in the fetal and adult brain.

Recently, published data have shown that EMP3 plays a role in the immune system. Overexpression of EMP3 in macrophages inhibits CD8⁺ cytotoxic T lymphocytes (CTLs), which are involved in tumor progression, viral infection, and type IV allergy. In contrast, knockdown of EMP3 expression enhances the induction of CTLs, secretion of interferon-γ, and the expression of IL-2 receptor α by CD8⁺ T cells. These findings represent the unique function of EMP3 in regulating the immune system via the inhibition of CTL induction.