# K-Ras sumoylation in cell proliferation and transformation

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2021 · $484,800

## Abstract

ABSTRACT
 Ras proteins are GTPases that activate multiple signaling cascades, which modulate cell
survival, proliferation, migration, and differentiation. Ras proteins are regulated by almost all
known post-translational modifications, including farnesylation, palmitoylation, phosphorylation,
ubiquitination, and acetylation. However, it remains unknown whether Ras proteins are modified
by sumoylation. We recently discovered that all three forms of Ras protein are SUMO3-modified.
Our further studies reveal that lysine 42 (K42) is the primary residue for sumoylation, whereas
PIASγ and MEKK1 are candidate E3 ligases that sumoylate Ras. Sumoylation is essential for
activating K-Ras and its downstream signaling. Furthermore, we have discovered a series of
SUMO E1 inhibitors that target SUMO conjugation both in vitro and in vivo. The lead compounds
27A and SB-264 potently inhibit sumoylation, but not ubiquitination or neddylation. Significantly,
these compounds display excellent bioactivities toward killing transformed pancreatic cells with
K-Ras mutations at glycine 12 or glycine 13 and suppress their migration. Given the role of
sumoylation in controlling functions of key cellular regulators and the paramount importance of K-
Ras in cell proliferation and transformation, we hypothesize that sumoylation promotes K-Ras
activity and that the SUMO regulatory pathway is an excellent target for development of anti-
cancer drugs. Three Specific Aims are proposed to test the validity of the hypothesis. We will
determine the mechanism by which sumoylation regulates K-Ras activation, elucidate the
regulatory network that controls K-Ras sumoylation, and investigate the efficacy of SUMO E1
inhibitors in suppressing proliferation of pancreatic cancer growth in preclinical mouse models.
Further characterization of K-Ras sumoylation promises to have a profound impact on our
understanding of the fundamental cellular signaling mechanisms that regulate cell growth. Given
the discovery of novel SUMO E1 inhibitors, our proposed studies will help to accelerate the
development of therapeutic applications that target ubiquitin-like modifications.
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## Key facts

- **NIH application ID:** 10169374
- **Project number:** 5R01CA216987-05
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Yuan Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $484,800
- **Award type:** 5
- **Project period:** 2017-06-15 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10169374

## Citation

> US National Institutes of Health, RePORTER application 10169374, K-Ras sumoylation in cell proliferation and transformation (5R01CA216987-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10169374. Licensed CC0.

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