RAS GTPases are modified by SUMOylation
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Byeong Hyeok Choi1, Changyan Chen3, Mark Philips4 and Wei Dai1,2
1Department of Environmental Medicine, New York University Langone Medical Center, New York, NY, USA
2Department of Biochemistry and Molecular Pharmacology, New York University Langone Medical Center, New York, NY, USA
3Center for Drug Discovery, Northeastern University, Boston, MA, USA
4Department of Pathology, New York University Langone Medical Center, New York, NY, USA
Wei Dai, email: [email protected]
Keywords: RAS; sumoylation; post-translational modification; oncogenesis
Received: October 07, 2017 Accepted: November 19, 2017 Published: December 15, 2017
RAS proteins are GTPases that participate in multiple signal cascades, regulating crucial cellular processes including cell survival, proliferation, differentiation, and autophagy. Mutations or deregulated activities of RAS are frequently the driving force for oncogenic transformation and tumorigenesis. Given the important roles of the small ubiquitin-related modifier (SUMO) pathway in controlling the stability, activity, or subcellular localization of key cellular regulators, we investigated here whether RAS proteins are posttranslationally modified (i.e. SUMOylated) by the SUMO pathway. We observed that all three RAS protein isoforms (HRAS, KRAS, and NRAS) were modified by the SUMO3 protein. SUMOylation of KRAS protein, either endogenous or ectopically expressed, was observed in multiple cell lines. The SUMO3 modification of KRAS proteins could be removed by SUMO1/sentrin-specific peptidase 1 (SENP1) and SENP2, but not by SENP6, indicating that RAS SUMOylation is a reversible process. A conserved residue in RAS, Lys-42, was a site that mediates SUMOylation. Results from biochemical and molecular studies indicated that the SUMO-E3 ligase PIASγ specifically interacts with RAS and promotes its SUMOylation. Moreover, SUMOylation of RAS appeared to be associated with its activation. In summary, our study reveals a new posttranslational modification for RAS proteins. Since we found that HRAS, KRAS, and NRAS can all be SUMOylated, we propose that SUMOylation might represent a mechanism by which RAS activities are controlled.
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