# Proteostasis at cellular membranes

> **NIH NIH R35** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2020 · $399,750

## Abstract

Project Summary
Cellular membranes not only compartmentalize intracellular processes but also serve as the dynamic hubs for
the assembly of many multi-protein signaling complexes, oncoproteins, and tumor suppressors. Accordingly, a
majority of current therapeutics (>60%) target membrane proteins that make up approximately 23% of human
proteome. In response to environmental cues and pharmacological drugs, the protein complement of cellular
membranes is altered to mount a calibrated response, which, if perturbed, impacts the disease state, e.g.,
cancer, cardiac and neurological disorders. The ubiquitin-proteasome system (UPS) aptly fits the task to swiftly
turnover the regulatory proteins with unmatched precision. To date, our understanding of the molecular details
of how membrane protein turnover is regulated by UPS-mediated proteolysis remain sketchy.
We are conducting the mechanistic studies in the investigations of novel UPS-regulated protein degradation
pathways at membranes modeled on our previous work with FBXL2, a highly conserved F-box protein
containing a typical C-terminal CaaX prenylation motif for localization to cellular membranes. The integrity of
the CaaX motif is necessary for FBXL2 to assemble into an active SCF ubiquitin ligase complex and interact
with two substrates, p85β and IP3R3, at cellular membranes. Interestingly, we recently discovered GGtase3, a
new mammalian prenyltransferase and identified FBXL2-ubiquitin ligase as the physiological target for
prenylation by GGTase3. This proposal uses an interdisciplinary approach to investigate the regulation and
biological relevance of membrane anchored protein turnover by UPS in mammalian cell survival and
proliferation, and full characterization of GGtase3 biology.

## Key facts

- **NIH application ID:** 9986254
- **Project number:** 1R35GM137452-01
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Shafi M. Kuchay
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $399,750
- **Award type:** 1
- **Project period:** 2020-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9986254

## Citation

> US National Institutes of Health, RePORTER application 9986254, Proteostasis at cellular membranes (1R35GM137452-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9986254. Licensed CC0.

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