The ubiquitin ligase Nedd4 is an ubuiquitin ligase (E3) which belongs to the HECT family. Like other member of this family members, such as Itch and Smurf, Nedd4 has been proposed to regulate a number of signaling pathways, as well as the traffic of several cell surface molecules, however, its physiological role in mammals has not been well characterized. Former reports identified reduction in the mitogenic activity and increase of the adaptor protein Grb10, aberrant IGF-1, VEGF and FGF receptor localization and / or signaling. In the present study, we performed an analysis of Nedd4-null murine embryonal fibroblastoid cells (MEFs) to show that loss of Nedd4 may affect any additional growth factor signaling. Surface expression of PDGF receptor was significantly increased in homozygous mutant mouse embryonic fibroblasts. Accordingly, PDGF-BB stimulation induced enhanced signaling as judged by MAP kinase p42/44 and Akt phosphorylation. Knockdown of Nedd4 in cell lines also induced similar phenotype. Nedd4, when transiently expressed, ubiquitinated PDGF receptor, which lead to degradation. Under the presence of lysosome inhibitors, PDGF receptor down regulation was at least partially blocked, suggesting its lysosome-dependent degradation. Subcellular localization of the PDGF receptor was also analyzed, but apparent difference was not observed. In the scratch assay, Nedd4 knockout cells showed enhanced migration activity, suggesting their active movement. Thus, Nedd4 appears to negatively control PDGF signaling partly through the regulation of its lysosome dependent degradation.

Citation Format: Nobuyuki Tanaka, Kyoko Oyama, Keiichi Tamai. Nedd4 controls cell migration by regulating PDGF receptor signaling. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4281. doi:10.1158/1538-7445.AM2013-4281