# Functional analysis of a tissue context-dependent role for beta-TRCP in lipid metabolism and tumorigenesis

> **NIH NIH R01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2020 · $374,063

## Abstract

Proper cell cycle transitions are driven by coordinated waves of ubiquitin-dependent degradation of key cell cycle regulators by APC/C and SCF E3 ubiquitin ligase complexes. Among them, SCFβ-TRCP is one of the well-characterized Cullin 1-based E3 ubiquitin ligases involved in numerous important cellular processes through promoting the degradation of critical regulatory proteins including -catenin, Emi1 and IBs. During the last funding cycle, our group and others have made significant contributions to further our understanding of the critical role of β-TRCP in various physiological functions such as autophagy, cell migration, DNA damage response and cell cycle regulation by defining DEPTOR, VEGFR, Mdm2 and Cdh1, respectively, as downstream substrates of SCFβ-TRCP. However, it remains largely unknown how upstream signaling pathways control β-TRCP stability and physiological functions in vivo. To this end, our preliminary results reveal that like Fbw7, β-TRCP undergoes auto-ubiquitination to negatively control its own stability, while OTUD3, but not other OTU family of DUBs, specifically interacts with, and deubiquitinates, β-TRCP to control its stability. As such, depletion of OTUD3 significantly reduced β-TRCP abundance. In Aim #1, we intend to explore mechanistically how the β-TRCP signaling pathway is governed by the dynamic auto-uibiquitination and deubiquitination processes to influence biological functions of β-TRCP in vivo. Furthermore, other than tissue context-dependent roles for β-TRCP in tumorigenesis, the physiological role of β-TRCP in metabolism such as lipid homeostasis has not been described. We reasoned that identification of additional β-TRCP ubiquitin substrate(s) would further define its physiological functions. To overcome the concern of using ectopic overexpression conditions in most E3 ligase-substrate screenings, we developed a novel screening system to identify β-TRCP substrates at endogenous levels using a β-TRCP phospho-degron specific antibody- mediated mass spectrometry approach. We identified many known β-TRCP targets, validating this screening method, and characterized Lipin1 and Lyric as novel β-TRCP substrates. This finding provides a novel link between β-TRCP and tissue-specific metabolic phenotypes observed in β-TRCP1-/- mice. Therefore, another major focus is to explore mechanistically how β-TRCP controls hepatocyte lipid metabolism through regulating Lipin1 protein stability and subsequent inhibition of SREBP1 transcriptional activity (Aim # 2). Lastly, we also intend to reveal a critical physiological role for β-TRCP in controlling enterocyte lipid absorption pathways and tumorigenesis by governing Lyric protein stability (Aim #3). We believe that these proposed studies will significantly extend our understanding of how β-TRCP exerts tissue context-dependent roles to control important process such as lipid metabolic pathways, and further implicate that in addition to tumorigenesis, aberrant regulation of -TR...

## Key facts

- **NIH application ID:** 9875450
- **Project number:** 5R01CA229307-07
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** Wenyi Wei
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $374,063
- **Award type:** 5
- **Project period:** 2012-05-01 → 2021-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9875450

## Citation

> US National Institutes of Health, RePORTER application 9875450, Functional analysis of a tissue context-dependent role for beta-TRCP in lipid metabolism and tumorigenesis (5R01CA229307-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9875450. Licensed CC0.

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