title: Dysregulation of ezrin phosphorylation prevents metastasis and alters cellular metabolism in osteosarcoma.
abstract: Ezrin links the plasma membrane to the actin cytoskeleton where it plays a pivotal role in the metastatic progression of several human cancers; however, the precise mechanistic basis for its role remains unknown. Here, we define transitions between active (phosphorylated open) and inactive (dephosphorylated closed) forms of Ezrin that occur during metastatic progression in osteosarcoma. In our evaluation of these conformations we expressed C-terminal mutant forms of Ezrin that are open (phosphomimetic T567D) or closed (phosphodeficient T567A) and compared their biologic characteristics to full-length wild-type Ezrin in osteosarcoma cells. Unexpectedly, cells expressing open, active Ezrin could form neither primary orthotopic tumors nor lung metastases. In contrast, cells expressing closed, inactive Ezrin were also deficient in metastasis but were unaffected in their capacity for primary tumor growth. By imaging single metastatic cells in the lung, we found that cells expressing either open or closed Ezrin displayed increased levels of apoptosis early after their arrival in the lung. Gene expression analysis suggested dysregulation of genes that are functionally linked to carbohydrate and amino acid metabolism. In particular, cells expressing closed, inactive Ezrin exhibited reduced lactate production and basal or ATP-dependent oxygen consumption. Collectively, our results suggest that dynamic regulation of Ezrin phosphorylation at amino acid T567 that controls structural transitions of this protein plays a pivotal role in tumor progression and metastasis, possibly in part by altering cellular metabolism.
authors.affiliation: Tumor and Metastasis Biology Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Ren
authors.forename: Sung-Hyeok
authors.initials: SH
authors.lastname: Hong
authors.forename: Qing-Rong
authors.initials: QR
authors.lastname: Chen
authors.forename: Joseph
authors.initials: J
authors.lastname: Briggs
authors.forename: Jessica
authors.initials: J
authors.lastname: Cassavaugh
authors.forename: Satish
authors.initials: S
authors.lastname: Srinivasan
authors.forename: Michael M
authors.initials: MM
authors.lastname: Lizardo
authors.forename: Arnulfo
authors.initials: A
authors.lastname: Mendoza
authors.forename: Ashley Y
authors.initials: AY
authors.lastname: Xia
authors.forename: Narayan
authors.initials: N
authors.lastname: Avadhani
authors.forename: Javed
authors.initials: J
authors.lastname: Khan
authors.forename: Chand
authors.initials: C
authors.lastname: Khanna
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary*; D051379:Mice; D018715:Microscopy, Video / Q000379:methods; D009154:Mutation; D012516:Osteosarcoma / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary*; D010641:Phenotype; D010766:Phosphorylation; D011487:Protein Conformation; D000099149:Ezrin
chemical_list: D003598:Cytoskeletal Proteins; D000099149:Ezrin