# The Fbw7 ubiquitin ligase network: normal and neoplastic functions

> **NIH NIH R01** · FRED HUTCHINSON CANCER CENTER · 2024 · $468,313

## Abstract

This application focuses on Fbw7, an E3 ubiquitin ligase and tumor suppressor, and on its substrate c-Myc
(hereafter, Myc), an oncogenic transcription factor widely implicated in human cancers. E3 ligases mark
protein substrates for degradation through ubiquitin conjugation. Fbw7 recognizes a network of proteins with
crucial roles in proliferation, differentiation, metabolism, and apoptosis. Fbw7 substrates include important
oncoproteins (e.g., cyclin E, Notch, Myc, Jun) and thus Fbw7 mutations promote tumorigenesis by
deregulating its oncogenic substrates. The Fbw7 pathway therefore has broad implications for cancer
biology and for the development of new therapeutic strategies. We will address important and unresolved
aspects of this pathway in two general areas. The first involves how phosphorylation and Fbw7 control Myc
stability and activity, in both normal cells and in cancers. The second area will address new paradigms in
the ways that Fbw7 recognizes substrates and how these interactions may underlie Fbw7 mutations in
cancers. This proposal may thus impact many areas of research related to Myc and the Fbw7 pathway.
Fbw7 binds substrates after they are phosphorylated within motifs termed degrons, that typically contain two
phosphorylated residues that interact with Fbw7. The first two Aims are focused on Myc regulation by
phosphorylation of a newly discovered Myc T244 degron that acts in concert with the canonical Myc T58
degron to bind Fbw7 dimers. Aim 1 will study how T244 degron phosphorylation is regulated in normal and
tumor cells and whether hierarchical Myc T244 degron phosphorylation controls Myc stability, as well as
how the T58 and T244 degrons are coordinately regulated by mitogenic and oncogenic signaling pathways.
Aim 2 will study the functions of the T244 degron in normal cells and tumorigenesis and how it cooperates
with the T58 degron. This will be accomplished through physiologic knockin models, in human cells and
mice, to create engineered Myc mutations that ablate Myc degron phosphorylations. Aim 3 will study how
Fbw7 dimers interact with substrates and how these interactions underlie Fbw7 mutations and their
functions in cancers. This includes determining the extent to which two separate degrons are required for
degradation across the Fbw7 substrate network. Identifying these new degrons may lead to entirely new
pathways that control the degradation of critical substrates and that may be abnormal in cancer cells.
Tumors often have heterozygous Fbw7 missense mutations that dimerize with wt-Fbw7, and the hypothesis
that these mutations specifically stabilize oncogenic substrates that require two degrons will be tested.
Finally, the Myc T244 degron binds Fbw7 through a novel mode that involves Fbw7 R689, a tumor hotspot,
and the role of R689 in dimer-dependent selective substrate recognition will be studied, as well as similar
possible functions for other Fbw7 missense mutations.

## Key facts

- **NIH application ID:** 10849737
- **Project number:** 5R01CA280280-02
- **Recipient organization:** FRED HUTCHINSON CANCER CENTER
- **Principal Investigator:** Bruce E Clurman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $468,313
- **Award type:** 5
- **Project period:** 2023-06-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10849737

## Citation

> US National Institutes of Health, RePORTER application 10849737, The Fbw7 ubiquitin ligase network: normal and neoplastic functions (5R01CA280280-02). Retrieved via AI Analytics 2026-05-31 from https://api.ai-analytics.org/grant/nih/10849737. Licensed CC0.

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