# Mechanisms of protein degradation that control signal transduction by Ras-Raf-MEK-ERK

> **NIH NIH R03** · UNIVERSITY OF WISCONSIN MILWAUKEE · 2021 · $76,000

## Abstract

Project Summary
 This proposal aims to discover mechanistic insights into how signal transduction by the highly
conserved Ras-Raf-MEK-ERK pathway is modulated by regulated protein degradation. In humans, mutation
of the gene BRAF, encoding one of three human Rafs, is a driver event in the development of malignant
melanoma. Indeed, the mutation BRAF(V600E) confers constitutive kinase activation and is one of the most
frequent mutations found in this cancer. Melanoma growth can be suppressed by inhibition of Raf kinase
activity. However, development of drug resistance and disease relapse occurs frequently, indicating that truly
effective treatments will require additional drug strategies. Our work, utilizing Caenorhabditis elegans as a
simple model to investigate signal transduction by this conserved pathway, demonstrates that C. elegans Raf
signaling is kept in check by inhibitory mechanisms that include phosphorylation and protein degradation (de
la Cova and Greenwald, 2012). For this proposed research, we use the C. elegans model to design and begin
an RNAi screen to identify conserved kinases and phosphatases that regulate Raf. We find that CDK2 is
necessary for Raf protein degradation, and that loss of CDK2 enhances phenotypes caused by a mutant,
activated Raf engineered to carry the same mutation as BRAF(V600E). Our long-term goal is to identify new
molecular targets for the development of drugs capable of inhibiting Raf signaling. Toward this goal, our
overall objectives in this application are to (i) identify additional kinases and phosphatases that impact Raf
protein degradation and their requirement for regulating BRAF in human cells, and (ii) determine the
mechanism and consequences of Raf regulation by the kinase CDK2. Our central hypothesis is that
conserved mechanisms, such as phosphorylation of the Raf protein, act to prevent aberrant Raf activation.
The rationale for this project is that our discovery of inhibitory control mechanisms governing signal
transduction by the Ras-Raf-MEK-ERK pathway will inform new strategies of drug therapy for melanoma.

## Key facts

- **NIH application ID:** 10201167
- **Project number:** 1R03CA248684-01A1
- **Recipient organization:** UNIVERSITY OF WISCONSIN MILWAUKEE
- **Principal Investigator:** Claire de la Cova
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $76,000
- **Award type:** 1
- **Project period:** 2021-06-04 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10201167

## Citation

> US National Institutes of Health, RePORTER application 10201167, Mechanisms of protein degradation that control signal transduction by Ras-Raf-MEK-ERK (1R03CA248684-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10201167. Licensed CC0.

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