title: 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.
authors.affiliation: Tumor and Metastasis Biology Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Briggs
authors.forename: Ling
authors.initials: L
authors.lastname: Ren
authors.forename: Rachel
authors.initials: R
authors.lastname: Nguyen
authors.forename: Kristi
authors.initials: K
authors.lastname: Chakrabarti
authors.forename: Jessica
authors.initials: J
authors.lastname: Cassavaugh
authors.forename: Said
authors.initials: S
authors.lastname: Rahim
authors.forename: Gulay
authors.initials: G
authors.lastname: Bulut
authors.forename: Ming
authors.initials: M
authors.lastname: Zhou
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Veenstra
authors.forename: Qingrong
authors.initials: Q
authors.lastname: Chen
authors.forename: Jun S
authors.initials: JS
authors.lastname: Wei
authors.forename: Javed
authors.initials: J
authors.lastname: Khan
authors.forename: Aykut
authors.initials: A
authors.lastname: Uren
authors.forename: Chand
authors.initials: C
authors.lastname: Khanna
mesh_terms: D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D047468:Immunoprecipitation; D009361:Neoplasm Invasiveness; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D014176:Protein Biosynthesis / Q000502:physiology*; D034741:RNA, Small Interfering; D053719:Tandem Mass Spectrometry; D014162:Transfection; D000099149:Ezrin
chemical_list: D003598:Cytoskeletal Proteins; D034741:RNA, Small Interfering; D000099149:Ezrin