# Heavy metal-stimulated signal transduction: new metal-regulatory and -responsive mechanisms

> **NIH NIH K99** · UNIVERSITY OF CHICAGO · 2023 · $87,588

## Abstract

PROJECT SUMMARY/ABSTRACT
From a human physiological perspective, heavy metals (HM) are divided into two groups: essential (eHM) and
toxic (tHM). eHM and tHM overexposure are both linked to numerous pathophysiological conditions; however,
the signal transduction pathways and genomic activities stimulated by eHM dyshomeostasis and tHM exposure
have yet to be adequately established. For example, the mammalian Cu-sensor protein responsible for relaying
changes in extracellular Cu levels into signaling responses has not been identified. The goals of this application
are to define (i) eHM- and tHM-stimulated and -regulatory signaling networks (including resultant genomic
activities), and (ii) the underlying molecular biological, biochemical, and biophysical mechanisms. Through the
work in this application, I have characterized the signaling and genomic responses induced by Cu exposure and
identified a mechanism of Cu-stimulated epidermal growth factor receptor (EGFR, a cell surface receptor tyrosine
kinase (RTK)) signal transduction along the MAPK/ERK pathway, thereby identifying EGFR as a candidate Cu-
sensor protein. Biochemical experiments are underway investigating the EGFR-Cu binding site and geometry.
Relatedly, through application of newly-developed next generation sequencing (NGS), molecular biological, and
transcriptomic (in vitro and in vivo) techniques, I discovered a novel mechanism by which intracellular Cu levels
are regulated. Elevated extracellular Cu levels stimulate EGFR/MAPK/ERK activation, which induces expression
of the transcription factor (TF) EGR1 and EGR1-corepressor NAB1/2; the EGR1-NAB1/2 complex subsequently
represses transcription of the mammalian Cu-importer, CTR1. EGR1 ChIP-seq experiments are underway for
further corroboration. This work will pair with experiments assessing synergism of an inhibitor of Cu-chaperones
and MAPK/ERK signaling (to increase CTR1 levels) with a platinum anticancer drug (cisplatin, imported via
CTR1), as well as genomic insights into the TF activities of EGR1 in EGFR-driven lung cancer (a role that is
currently unknown). My research establishing the Cu-regulatory network lays the foundation for my planned
independent career (i) evaluating eHM- and tHM-regulatory and -responsive mechanisms and (ii) characterizing
disruption of native signaling by tHM. In my independent career, I will apply phosphorylation arrays and NGS
techniques to cells stimulated with non-Cu eHM and high-priority environmental pollutant tHM, with emphasis on
the effects of tHM exposure in disrupting the eHM-regulatory and -responsive signal transduction networks. In
summary, my identification of EGFR as a conduit for relaying elevated extracellular Cu levels into genomic
activities via the MAPK/ERK pathway has linked a major signal transduction network (implicated in cancer
pathophysiology, for example) to eHM-regulation, and thereby opens new avenues of understanding HM-
regulatory networks in general. More broadly, the comp...

## Key facts

- **NIH application ID:** 10592144
- **Project number:** 1K99ES034084-01A1
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Matthew Oliver Ross
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $87,588
- **Award type:** 1
- **Project period:** 2022-12-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10592144

## Citation

> US National Institutes of Health, RePORTER application 10592144, Heavy metal-stimulated signal transduction: new metal-regulatory and -responsive mechanisms (1K99ES034084-01A1). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10592144. Licensed CC0.

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