The Ezrin Metastatic Phenotype Is Associated with the Initiation of Protein Translation

Abstract

We previously associated the cytoskeleton linker protein, Ezrin, with the metastatic phenotype of pediatric sarcomas, including osteosarcoma and rhabdomyosarcoma. These studies have suggested that Ezrin contributes to the survival of cancer cells after their arrival at secondary metastatic locations. To better understand this role in metastasis, we undertook two noncandidate analyses of Ezrin function including a microarray subtraction of high-and low-Ezrin-expressing cells and a proteomic approach to identify proteins that bound the N-terminus of Ezrin in tumor lysates. Functional analyses of these data led to a novel and unifying hypothesis that Ezrin contributes to the efficiency of metastasis through regulation of protein translation. In support of this hypothesis, we found Ezrin to be part of the ribonucleoprotein complex to facilitate the expression of complex messenger RNA in cells and to bind with poly A binding protein 1 (PABP1; PABPC1). The relevance of these findings was supported by our identification of Ezrin and components of the translational machinery in pseudopodia of highly metastatic cells during the process of cell invasion. Finally, two small molecule inhibitors recently shown to inhibit the Ezrin metastatic phenotype disrupted the Ezrin/PABP1 association. Taken together, these results provide a novel mechanistic basis by which Ezrin may contribute to metastasis.

Role of Ezrin in Osteosarcoma Metastasis

“…In support of this hypothesis, ezrin was found to be part of the ribonucleoprotein complex, to facilitate the expression of complex mRNAs in cells and to bind with poly A binding protein 1 (PABA1; PABPC1 ). These fi ndings were further supported by the identifi cation of ezrin and components of the translational machinery in pseudopodia of highly metastatic cells during the process of cell invasion [ 118 ]. In addition, two small molecule inhibitors recently shown to inhibit the ezrin metastatic phenotype disrupted the Ezrin/PABP1 association [ 119 ].…”

Ezrin Inhibition Up-regulates Stress Response Gene Expression

“…This form of ezrin is regarded as fully functional; it can bind various membraneassociated proteins and the underlying cortical F-actin via its N-terminal and C-terminal domains, respectively. Recent data from our lab has demonstrated that the function of ezrin extends beyond its classical role as a cross-linker protein at the membrane-cortex interface to bind with DDX3 as a modulator of translation (21,22). Thus, our prior findings suggested that ezrin has a role in integrating cellular stress response with the regulation of mRNA translation, thereby possibly rendering the cells more resistant to oncogenic stress encountered during metastatic progression (21).…”

The clinical significance of changes in ezrin expression in osteosarcoma of children and young adults

“…Ezrin interacts directly with adhesion-related proteins such as CD43, CD44, CD95, ICAM-1, -2, -3 and PA2.26 antigen [9], binds to adapter proteins such as EBP50/NHE-RF and E3KARP [10,11], associates with cytoplasmic signaling proteins, and is involved in several signaling pathways, such as Rho and PI3K/Akt [12]. Ezrin thus takes part in cell adhesion, motility, phagocytosis and the dynamics of membrane transport [13].…”