Here we report for the first time that TMEFF2 high throughput screening selectively interacts with PDGF-AA via its follistatin domain�Ccontaining extracellular regions, and modulates PDGFAA�C stimulated proliferation of NR6 fibroblasts. Interestingly, both shedding of the extracellular domains of TMEFF2, and a truncated splice variant of TMEFF2 encoding a secreted protein without the EGF-like and the transmembrane domains, have been identified in cells, suggesting a possible functional role of the extracellular region containing the follistatin domains independent of the intracellular and transmembrane regions. First identified in a search for serum factors that stimulate the proliferation of arterial smooth muscle cells, PDGFs have been shown to direct a variety of cellular responses including proliferation, survival, migration, and the deposition of ECM and CPI-613 clinical trial tissue remodeling factors. Of the genes encoding the four PDGF ligands and their two receptor chains, mouse knockout studies have suggested that PDGF-B and PDGFR? are essential for the development of support cells in the vasculature, whereas PDGF-A and PDGFRa are more broadly required during embryogenesis, with essential roles in central nervous system, neural crest and organ development. PDGFs have also been implicated in the etiology of human cancers. Both PDGFs and PDGFRs are upregulated in human gliomas and astrocytomas, and PDGFRa mRNA expression levels are higher in more advanced forms of gliomas than in less malignant glial tumors. Elevated levels of PDGF-A and PDGFRa proteins have also been observed in human prostate carcinomas. In human gastric cancers, high levels of PDGF-A correlate with high-grade carcinomas and reduced patient survival. Pdgfra-activating mutations have also been identified in a subset of human gastrointestinal stromal tumors. Interestingly, we and others have observed highest levels of TMEFF2 expression in the central nervous system and the prostate amongst normal human tissues. Conversely, lower levels of TMEFF2 are found in multiple cancer tissues, especially in the malignant brain and colorectal samples, when compared to normal tissues. The significance of the previously reported hypermethylation of TMEFF2 gene in human cancers including colorectal, gastric and esophageal cancers is confounded by the low levels of TMEFF2 expression in normal tissues of these origins. Here we report hypermethylation of TMEFF2 in several additional tumor types, including GBM, where a clear down-regulation is observed compared to high levels of TMEFF2 expression in normal brain tissues. We show that expression of TMEFF2 negatively correlates with its methylation levels in GBM and several other tumor types, further supporting a possible tumor suppressor role of TMEFF2 in these tissues.