Ezrin, a member of the ERM (ezrin/radixin/moesin) family of proteins, is a ~80kD mediator of the interaction between actin filaments and the plasma membrane. In its interaction with the cytoskeleton, ezrin is involved in the formation of microvilli, cell-cell adhesion, cell shape, motility, membrane trafficking, and signal transduction. Ezrin is composed of a C-terminal actin-binding domain, an alpha-helical region, and an N-terminal domain that interacts with CD43, CD44, ICAM-1, ICAM-2, and PIP2 (phosphatidylinositol 4,5-biphosphate). Ezrin’s function is regulated by its conformation; the amino- and carboxy-termini associate head-to-tail, blocking the F-actin binding domain in ezrin’s native conformation. Merlin, the protein product of the tumor suppressor gene neurofibromatosis-2 (NF2), also binds to ezrin in this head-to-tail orientation. Phosphorylation of threonine and tyrosine residues has been implicated in ezrin protein activity. Ezrin phosphorylation has been reported on tyrosine residues after growth factor stimulation, and the phosphorylation of a conserved threonine (T567) is recognized as a key regulator in the transition from membrane-bound ezrin oligomers to active monomers, which induce the formation of actin-rich membrane projections. Because of its role in cell migration and recognition by the immune system, ezrin expression has been studied in a variety of normal and malignant tissues and cell lines. Ezrin is localized intracellularly under the plasma membrane in microvilli and at sites of cell-cell contact; normal tissues with high levels of expression include intestine, kidney, and placenta. In cell lines, ezrin expression has been observed in endometrial, pancreatic, colorectal, and breast carcinomas, and tissue expression has been described in uveal melanoma, the stromal cells of hemangioblastoma (but not glioblastoma), and astrocytoma (but not oligodendroglioma).