# Regulation of the ERK signaling pathway by K63-linked polyubiquitination

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $384,394

## Abstract

PROJECT SUMMARY/ABSTRACT
The overall goal of this application is to elucidate the mechanism of Lys63 (K63)-linked polyubiquitination of
extracellular signal-regulated kinases ERK1 and ERK2, and to determine the contribution of this novel post-translational
modification to tumorigenesis. ERK1 and ERK2, which share high structural and functional
similarities, are downstream effectors of a mitogen-activated protein kinase (MAPK) cascade that dictates
cellular behavior and cell fate decisions in response to a wide range of intracellular signals. The ERK signaling
pathway is the primary mitogenic pathway in mammalian cells. It is aberrantly upregulated in a large fraction of
human tumors due to prevalence of mutations in the upstream signaling components, and reactivation of ERK
is also the most common mechanism for resistance to drugs that target these upstream components. Developing
a therapy that is applicable for the wide range of tumors driven by a hyperactive ERK pathway and that can
circumvent drug resistance remains a major challenge in cancer research. To contend with this challenge
requires a comprehensive understanding of how ERK is specifically and efficiently activated within the MAPK
cascade. The current knowledge of ERK activation is largely limited to their phosphorylation by the upstream
kinase MEK. In our preliminary studies, we have found that ERK is conjugated to K63-linked polyubiquitin chains,
and that this post-translational modification correlates with ERK activation. Furthermore, we have identified the
tripartite-motif protein TRIM15 as a ubiquitin ligase, and the tumor suppressor CYLD as a deubiquitinating
enzyme (DUB), that may dynamically regulate ERK ubiquitination. Here we will test the central hypothesis that
K63 ubiquitination of ERK is critical for the specific and efficient activation of these kinases and that dysregulation
of this post-translational modification contributes to the pathogenesis and therapeutic resistance of tumors. We
propose three specific aims. First, we will characterize the role of TRIM15 and CYLD in K63 ubiquitination of
ERK and define how their interactions with ERK are regulated by mitogenic stimuli. Second, we will elucidate
the function and mechanism of K63 ubiquitination in the activation of ERK. Third, we will determine the role of
TRIM15 and CYLD in tumorigenesis and therapeutic resistance. Collectively, these aims will address
fundamental issues in ERK biology and oncogenic signaling, and will provide valuable information for the
development of effective therapies for the plethora of human tumors that are driven by a hyperactive ERK
signaling pathway.

## Key facts

- **NIH application ID:** 10903731
- **Project number:** 5R01CA268645-03
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Xiaolu Yang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $384,394
- **Award type:** 5
- **Project period:** 2022-09-09 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10903731

## Citation

> US National Institutes of Health, RePORTER application 10903731, Regulation of the ERK signaling pathway by K63-linked polyubiquitination (5R01CA268645-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10903731. Licensed CC0.

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