title: TMEFF2 is a PDGF-AA binding protein with methylation-associated gene silencing in multiple cancer types including glioma.
abstract: BACKGROUND
  TMEFF2 is a protein containing a single EGF-like domain and two follistatin-like modules. The biological function of TMEFF2 remains unclear with conflicting reports suggesting both a positive and a negative association between TMEFF2 expression and human cancers.
  
  
  RESULTS
  Here we report that the extracellular domain of TMEFF2 interacts with PDGF-AA. This interaction requires the amino terminal region of the extracellular domain containing the follistatin modules and cannot be mediated by the EGF-like domain alone. Furthermore, the extracellular domain of TMEFF2 interferes with PDGF-AA-stimulated fibroblast proliferation in a dose-dependent manner. TMEFF2 expression is downregulated in human brain cancers and is negatively correlated with PDGF-AA expression. Suppressed expression of TMEFF2 is associated with its hypermethylation in several human tumor types, including glioblastoma and cancers of ovarian, rectal, colon and lung origins. Analysis of glioma subtypes indicates that TMEFF2 hypermethylation and decreased expression are associated with a subset of non-Proneural gliomas that do not display CpG island methylator phentoype.
  
  
  CONCLUSIONS
  These data provide the first evidence that TMEFF2 can function to regulate PDGF signaling and that it is hypermethylated and downregulated in glioma and several other cancers, thereby suggesting an important role for this protein in the etiology of human cancers.
authors.affiliation: Genentech, South San Francisco, California, United States of America. klin@gene.com
authors.forename: Kui
authors.initials: K
authors.lastname: Lin
authors.forename: James R
authors.initials: JR
authors.lastname: Taylor
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Wu
authors.forename: Johnny
authors.initials: J
authors.lastname: Gutierrez
authors.forename: J Michael
authors.initials: JM
authors.lastname: Elliott
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Vernes
authors.forename: Hartmut
authors.initials: H
authors.lastname: Koeppen
authors.forename: Heidi S
authors.initials: HS
authors.lastname: Phillips
authors.forename: Frederic J
authors.initials: FJ
authors.lastname: de Sauvage
authors.forename: Y Gloria
authors.initials: YG
authors.lastname: Meng
mesh_terms: D001932:Brain Neoplasms / Q000378:metabolism*; D049109:Cell Proliferation; D019175:DNA Methylation; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D005910:Glioma / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008565:Membrane Proteins / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D016366:Open Reading Frames; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015398:Signal Transduction
chemical_list: D008024:Ligands; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D010982:Platelet-Derived Growth Factor; C423567:TMEFF2 protein, human; C075278:platelet-derived growth factor A