# Rabex-5 regulation of Ras and Notch signaling in development and disease

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $326,288

## Abstract

SUMMARY
Ras signaling promotes proliferation, cell survival, and differentiation and is implicated in cancer. To devise
effective therapeutics, it is vital to understand how Ras is regulated and how to block its activity. My lab
discovered that modifying Ras by attaching the small protein ubiquitin restricts both wild-type and oncogenic
forms of Ras. Impairing Ras ubiquitination in vivo in Drosophila led to striking effects on cell proliferation, cell
survival, developmental patterning, and organismal longevity, reflecting a role for Ras ubiquitination in
development, tumor suppression, and survival. We identified the Ras E3 (the ubiquitin ligase that adds
ubiquitin to Ras) as Rabex-5 (also called RabGEF1). Intriguingly, we discovered that Rabex-5 also regulates
the Notch oncogene. The power of Drosophila genetics and the well-established paradigm of studying Ras in
Drosophila make this system ideally-suited to characterize these phenomena in a multi-cellular context. The
goal of this proposal is to use in vivo Drosophila studies and in vitro biochemical analysis to elucidate
the biological significance and molecular mechanisms of Ubiquitin Pathway regulation of Ras and
Notch signaling. Defining the molecular mechanism(s) of Ras ubiquitination will yield key insights into
fundamental biology and will reveal novel points of therapeutic entry in cancer. We made initial observations
regarding spatial and temporal regulation of Ras ubiquitination. Consistent with data that Rabex-5 is lost or
decreased in various cancers, our loss-of-function studies unambigiously indicate a tumor suppressor role for
Rabex-5 by inhibiting Ras and Notch signaling. We hypothesize that Rabex-5 restricts Ras and Notch and
acts in tumor suppression via its E3 domain. By complementing in vivo Drosophila work with in vitro
biochemistry, we are uniquely positioned to make significant advances into conserved, fundamental
mechanisms of regulation and coordination of Ras and Notch oncogenic signaling.

## Key facts

- **NIH application ID:** 9857038
- **Project number:** 5R01GM122995-04
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** CATHIE M PFLEGER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $326,288
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9857038

## Citation

> US National Institutes of Health, RePORTER application 9857038, Rabex-5 regulation of Ras and Notch signaling in development and disease (5R01GM122995-04). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/9857038. Licensed CC0.

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