# Identifying the mechanisms and biological impact of ERK lipidation in metabolic signaling

> **NIH NIH F30** · UNIVERSITY OF CHICAGO · 2021 · $51,036

## Abstract

Project Summary/Abstract
At the cellular level, impaired signaling cascades both contribute to and are characteristic of metabolic syndrome,
a constellation of interrelated disorders including hyperlipidemia and hyperglycemia. However, the mechanisms
of pathogenesis are complex, multifactorial, and incompletely described. Recent studies suggest a role for
protein S-palmitoylation, a dynamic lipid post-translational modification (PTM) that affects protein function and
activity, in the regulation of metabolic signaling events. As the addition of the palmitate lipid to cysteine is
dependent on lipid levels – which are in turn altered in metabolic syndrome – protein lipidation represents a
potential mechanistic link between aberrant nutrient factors and changes in signaling protein activity. We have
observed that the extracellular signal-regulated kinase (ERK), whose signaling-responsive activity regulates
cellular metabolism/energy homeostasis and is altered in metabolic syndrome, is subject to a rapid, signaling-
induced increase in palmitoylation. Moreover, the basal level of ERK palmitoylation is increased in a mouse
model of obesity, confirming that its lipidation status is sensitive to diet. In this project, with ERK as the focal
point, we aim to map the connections between regulatory S-palmitoylation, signal transduction, and the sequelae
of metabolic syndrome. In Aim 1, we will use a combination of molecular biological, biochemical, and chemical
approaches to determine the molecular mechanisms of ERK palmitoylation and to elucidate the impact of
dynamic S-palmitoylation on ERK-mediated signal transduction. In order to assess the contribution of increased
ERK palmitoylation to metabolic syndrome, in Aim 2 we will develop a chemical inhibitor of ERK S-palmitoylation.
We will then employ it in a mouse model of metabolic syndrome, evaluating changes in ERK activity and the
mitigation of markers of metabolic syndrome, including insulin resistance and circulating fatty acid levels. This
work will establish a novel regulatory framework for ERK, as well as new chemical tools for probing the
mechanisms and consequences of its activity. It will also provide a model for how dynamic protein lipidation can
function in cell signaling events and contribute to cellular pathophysiologies.
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## Key facts

- **NIH application ID:** 10127498
- **Project number:** 5F30DK125088-02
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Saara-Anne Azizi
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $51,036
- **Award type:** 5
- **Project period:** 2020-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10127498

## Citation

> US National Institutes of Health, RePORTER application 10127498, Identifying the mechanisms and biological impact of ERK lipidation in metabolic signaling (5F30DK125088-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10127498. Licensed CC0.

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