# Examining the Intersection of Transitional Metals and Kinase Signal Transduction Networks

> **NIH NIH R35** · UNIVERSITY OF PENNSYLVANIA · 2020 · $386,895

## Abstract

PROJECT SUMMARY/ ABSTRACT
Normal physiology relies on the precise coordination of intrinsic cues, in the form of intracellular signal
transduction pathways, with extrinsic cues like nutrient availability to balance cell growth and cell death.
Transition metals such as copper (Cu) are tightly regulated micronutrients that function as structural or catalytic
cofactors for proteins that are critical for normal physiology and development. Aberrant Cu excretion and
absorption are manifested in the extremely rare genetic diseases Wilson and Menkes, respectively. The
importance of intact Cu homeostatic mechanisms to cell growth control is underscored by the stunted growth
and failure to thrive associated with Cu deficiency in Menkes disease patients and the prevalence of cancer in
patients with hereditary Cu overload in Wilson disease. Further, Cu is neither created nor destroyed, and
therefore low Cu dietary intake may be a contributing factor in impaired wound healing, cardiovascular disease,
and non-alcoholic fatty liver disease. However, the dysregulation of a handful of currently identified Cu-
dependent enzymes does not fully explain the diverse growth phenotypes associated with alterations in Cu
metabolism. Thus, the direct cellular pathways that respond to and or/sense Cu abundance and are integrated
to influence cellular proliferation remain undefined. Recent work by our group uncovered an unexpected link
between the cellular acquisition of Cu and a mitogenic signaling cascade. In response to proliferative signals,
Cu contributes to the amplitude of canonical MAPK signaling through a direct interaction between Cu and the
kinases MEK1 and MEK2. This is the first example of Cu directly regulating the activity of a mammalian kinase
and has exposed a new signaling paradigm that directly connects Cu to signaling pathway components. Based
on our expertise, our group seeks to define the Cu-responsive and -sensing kinase signal transduction
pathways to determine the mechanisms by which Cu contributes to pro-proliferative cellular processes that are
essential to normal proliferation and are sustained during tumorigenesis. To accomplish our goals, we will
utilize a multidisciplinary approach, which includes in vivo mouse models, biochemistry, biophysics, molecular
biology, functional genomics, and pharmacologic interventions. Specifically, we will: i) elucidate the
molecular mechanisms and cellular contexts that underlie Cu integration into the MAPK pathway, ii)
systematically map Cu utilization by pro-proliferative kinase signal transduction pathways, and iii)
leverage our experimental approaches and findings to other transition metals and kinase signaling
networks in normal homeostasis and cancer. Completion of these studies has the potential to establish Cu
availability as an integral component of intracellular communication and elucidate the molecular mechanism
underlying this unique connection. Further, identifying novel Cu-dependent kinases can be ...

## Key facts

- **NIH application ID:** 9978887
- **Project number:** 5R35GM124749-04
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Donita C Brady
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $386,895
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9978887

## Citation

> US National Institutes of Health, RePORTER application 9978887, Examining the Intersection of Transitional Metals and Kinase Signal Transduction Networks (5R35GM124749-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9978887. Licensed CC0.

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