title: Phosphorylated ezrin is associated with EBV latent membrane protein 1 in nasopharyngeal carcinoma and induces cell migration.
abstract: Tumor metastasis is a complex phenomenon that is the culmination of effects of numerous cellular factors. We have shown that the Epstein-Barr virus (EBV) oncoprotein, latent membrane protein 1 (LMP1), is capable of inducing a wide range of such factors in cell culture, expression of which is also elevated in the LMP1-expressing tumor, nasopharyngeal carcinoma (NPC), a highly invasive neoplasm. Recently, the membrane crosslinker protein, ezrin, has been implicated in tumor cell metastasis and malignant progression. In this study, we evaluated the possible role of LMP1 and ezrin in the pathophysiology of NPC. We show that C-terminal phosphorylation of ezrin is increased by the expression of LMP1 in nasopharyngeal (NP) cells through a protein kinase C (PKC) pathway. LMP1 enhances the organization of a ternary complex of CD44, ezrin and F-actin, which is a prerequisite for ezrin phosphorylation. In NPC tissues, the expression of phosphoezrin and LMP1 is directly correlated. Silencing of endogenously expressed ezrin suppresses LMP1-induced cell motility and invasiveness. Moreover, the inhibition of ezrin phosphorylation by PKC inhibitor suppresses migration and invasion of NP cells. These data show that the phosphorylation of ezrin and its recruitment to the cell membrane linked to F-actin and CD44 is a process required for LMP1-stimulated cell motility and invasion of NP cells.
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599-7295, USA.
authors.forename: K
authors.initials: K
authors.lastname: Endo
authors.forename: S
authors.initials: S
authors.lastname: Kondo
authors.forename: J
authors.initials: J
authors.lastname: Shackleford
authors.forename: T
authors.initials: T
authors.lastname: Horikawa
authors.forename: N
authors.initials: N
authors.lastname: Kitagawa
authors.forename: T
authors.initials: T
authors.lastname: Yoshizaki
authors.forename: M
authors.initials: M
authors.lastname: Furukawa
authors.forename: Y
authors.initials: Y
authors.lastname: Zen
authors.forename: J S
authors.initials: JS
authors.lastname: Pagano
mesh_terms: D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement; D003598:Cytoskeletal Proteins / Q000502:physiology*; D003600:Cytosol / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D018960:Hyaluronan Receptors / Q000032:analysis; D009303:Nasopharyngeal Neoplasms / Q000473:pathology*; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D011493:Protein Kinase C / Q000502:physiology; D021381:Protein Transport; D014157:Transcription Factors / Q000378:metabolism; D014763:Viral Matrix Proteins / Q000502:physiology*; D054460:rho-Associated Kinases / Q000502:physiology; D000099149:Ezrin
chemical_list: D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D018960:Hyaluronan Receptors; D011493:Protein Kinase C; D014157:Transcription Factors; D014763:Viral Matrix Proteins; D054460:rho-Associated Kinases; D000099149:Ezrin; C497483:CD44 protein, human; C037662:EBV-associated membrane antigen, Epstein-Barr virus; C086680:ETV5 protein, human