# Deciphering the physiological role and interplay between ubiquitination and phosphorylation pathways to guide targeted cancer therapies

> **NIH NIH R35** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2021 · $1,050,000

## Abstract

Abstract
A vast majority of the 25,000 genes identified in the human genome are subjected to alternative splicing, and
their protein products are often heavily modified with posttranslational modifications including but not limited to
ubiquitination, phosphorylation, methylation, and acetylation, thereby vastly increasing the functional diversity of
the human proteome. However, aberrant cell signaling events caused by dysregulation of protein modifications
often lead to altered protein homeostasis and cellular function to facilitate the development of human diseases
including cancer. In keeping with a critical role for these modifications to governing tumorigenesis, inhibitors
targeting enzymes regulating these post-translational modifications have attracted extensive attention as
biomarkers and anti-cancer drug targets. To this end, the heart of my laboratory has been focused on studying
the regulatory mechanisms and physiological functions of two major multi-component protein enzyme
complexes: Cullin-based E3 ubiquitin ligase complexes and the Mammalian Target of Rapamycin Complex
(mTOR), as well as their interplay with other cell signaling pathways to govern cell cycle regulation and
tumorigenesis. The long-term goal of my research program is to understand how aberrant cell signaling pathways
including phosphorylation and ubiquitination influence tumorigenesis, which guides the identification of novel
drug targets for treating human cancers. Over the past thirteen years of independence, my laboratory has
established an outstanding track record of original, cutting-edge, research in the cell cycle and cancer signaling
fields. In this proposal, I have expanded our research by further deciphering the role of ubiquitination in regulating
the mTORC1 signaling pathway, as well as the interplay between ubiquitination and phosphorylation signaling
pathways to govern tumorigenesis, thereby providing mechanistic insights and the rationale to develop inhibitors
targeting key modules of cell signaling pathways including E3 ligases and kinases to enhance our capability of
creating highly targeted cancer therapies. To achieve these goals, one major theme is to use both biochemical
and genetic approaches to understand the oncogenic role of Skp2 and the tumor suppressive role of Fbw7 in
part via modulating cell metabolism through ubiquitination-mediated pathways. The second major theme of this
proposal aims to investigate the physiological and pathological impacts of GATOR2-mediated ubiquitination of
GATOR1 signaling events during cancer development in vivo, which will guide us to uncover novel therapeutic
opportunities targeting these signaling pathways. This prestigious award would therefore provide us the
necessary resources to use highly innovative approaches to tackle challenging questions such as understanding
the molecular and cellular mechanisms governing tumorigenesis to shed light on novel pathways to target cancer
more effectively. Receiving this p...

## Key facts

- **NIH application ID:** 10240580
- **Project number:** 5R35CA253027-02
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** Wenyi Wei
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,050,000
- **Award type:** 5
- **Project period:** 2020-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10240580

## Citation

> US National Institutes of Health, RePORTER application 10240580, Deciphering the physiological role and interplay between ubiquitination and phosphorylation pathways to guide targeted cancer therapies (5R35CA253027-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10240580. Licensed CC0.

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