TMEFF2 is a PDGF-AA binding protein with methylation-associated gene silencing in multiple cancer types including glioma |
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Authors: | Lin Kui Taylor James R Wu Thomas D Gutierrez Johnny Elliott J Michael Vernes Jean-Michel Koeppen Hartmut Phillips Heidi S de Sauvage Frederic J Meng Y Gloria |
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Institution: | Genentech, South San Francisco, California, United States of America. klin@gene.com |
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Abstract: | BackgroundTMEFF2 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.Methodology/Principal FindingsHere 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/SignificanceThese 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. |
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