TMEFF2 Is a PDGF-AA Binding Protein with Methylation-Associated Gene Silencing in Multiple Cancer Types Including Glioma

Kui Lin,Frederic J De Sauvage,Johnny Gutierrez,Jean-Michel Vernes,J Michael Elliott,Heidi S Phillips,James R Taylor,Hartmut Koeppen,Thomas D Wu,Y Gloria Meng

doi:10.1371/journal.pone.0018608

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.

Highlights

TMEFF2, known as tomoregulin [1], TPEF [2], HPP1 [3] and TENB2 [4], encodes a transmembrane protein that contains a single epidermal growth factor (EGF)-like domain and two follistatin-like modules [1,4,5,6]
While there was only a slight background binding between PDGFAA and the uncoated plastic wells, the binding of Platelet-derived growth factors (PDGFs)-AA to immobilized TECD-FLAG was comparable to its binding to an immobilized anti-PDGF antibody under the same conditions (Fig. 2A)
The follistatin domain–containing extracellular matrix (ECM)–associated glycoprotein SPARC/osteonectin was reported to interact with PDGF-AB and BB and inhibit the binding of these ligands to their cognate receptors on fibroblasts [19]

Summary

Introduction

TMEFF2, known as tomoregulin [1], TPEF [2], HPP1 [3] and TENB2 [4], encodes a transmembrane protein that contains a single epidermal growth factor (EGF)-like domain and two follistatin-like modules [1,4,5,6]. As evidence for its positive role in cell proliferation, elevated TMEFF2 expression has been associated with higher prostate cancer grade and hormone independence by several groups [4,7,8]. 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

Methods

Results

Conclusion