Nonsteroidal anti-inflammatory drug (NSAID)-activated gene (NAG-1, also known as GDF15) is a divergent member of the transforming growth factor-beta (TGF-β) superfamily, which exert their biological activity by binding to membrane receptors as a secretion protein. Abnormal regulation of TGF-β signaling can contribute to various diseases such as cancer. Although there is sequence similarity between NAG-1 and other TGF-β superfamily members, NAG-1 does not bind to the TGF-β receptors; therefore the biological consequence of NAG-1 remains to be elucidated. Here, we report that NAG-1 has two putative non-canonical nuclear localization signals (NLSs) that mediate NAG-1 nuclear localization. Nuclear import assay shows that NAG-1 enters the nucleus through nuclear pore complex (NPC) in the presence of ATP, indicating nuclear entry of NAG-1 is active transport. Furthermore, we found the nuclear export signal (NES) recognized by CRM1 at near N-terminal region of NAG-1, that is conserved across various mammalian species. Impeding NES via chemical or genetic approaches promotes nuclear accumulation of NAG-1. We also found that nuclear NAG-1 dampens TGF-β-mediated cell migration and invasion via the inhibition of DNA binding of Smads complex. Overall, our data suggest that nuclear NAG-1 affects TGF-β-induced metastasis activity in cancer cells.
Grant support: This work was supported by grant from the University of Tennessee Center of Excellence in Livestock Diseases and Human Health.
K Min, Current address: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA
Citation Format: Kyung-Won Min, Gabriel Silva, Seung J. Baek. Nuclear localization of a secretion protein NAG-1/GDF15. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2903.