Oncotarget

Research Papers:

RAS GTPases are modified by SUMOylation

Byeong Hyeok Choi, Changyan Chen, Mark Philips and Wei Dai _

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2018; 9:4440-4450. https://doi.org/10.18632/oncotarget.23269

Metrics: PDF 1330 views  |   HTML 1642 views  |   ?  


Abstract

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

Correspondence to:

Wei Dai, email: wei.dai@nyumc.org

Keywords: RAS; sumoylation; post-translational modification; oncogenesis

Received: October 07, 2017     Accepted: November 19, 2017     Published: December 15, 2017

ABSTRACT

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.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 23269