The loss of NF2 gene function leads to vestibular nerve schwannoma formation in humans. The NF2 gene product, Merlin/Schwannomin, has recently been found to interact with the two PDZ domains containing protein EBP50/NHE-RF, which is itself known to interact with the PDGF receptor (PDGFR) in several cell types. In this study, an up-regulation of both PDGFR and EBP50/NHE-RF, and an interaction of both proteins were found in primary human schwannoma tissue. Furthermore, using an adenoviral vector mediated gene transfer technique, changes in the phenotypic characteristics after NF2 gene restoration in a newly established NF2 gene-mutated human schwannoma cell line (HEI 193) were investigated. The overexpression of Merlin/Schwannomin in HEI 193 led to an inhibition of cell proliferation under serum-free conditions. Upon PDGF stimulation in culture, Merlin/Schwannomin appeared to inhibit the activation of the MAPK and PI3K signaling pathways, impinging on the phosphorylation of Erk 1/2 and Akt, respectively. The data also show that PDGFR is more rapidly internalized by the schwannoma cells overexpressing NF2. Therefore, this process is suggested as a model for a mechanism of Merlin/Schwannomin tumor suppressor function, which intermediates acceleration of the cell surface growth factor degradation.