# Notch Signaling in Cancer

> **NIH NIH R35** · HARVARD MEDICAL SCHOOL · 2022 · $996,608

## Abstract

Project Summary
The motivation for my research program has been to understand how oncogenic signaling promotes human
cancer. An important facet of our work, which distinguishes our contributions from those of others, is that we
have focused on fundamental questions about molecular mechanisms of both normal and aberrant signaling,
emphasizing structural, biochemical, molecular, and cell-based approaches. My overarching research goals over
the award period build from our sustained contributions over almost two decades in the Notch field, and will
emphasize answering the following key questions:
i) What is the molecular mechanism of normal and pathogenic Notch activation by ADAM-family proteases?
Ligands normally convert Notch receptors from a dormant to signaling-active state by rendering them susceptible
to proteolysis by ADAM-family metalloproteases at a site immediately external to the cell membrane, yet our
understanding of ADAM-mediated proteolysis of Notch receptors remains remarkably rudimentary. We will
elucidate the structures of the full ADAM10 and ADAM17 ectodomains, and determine how interplay between
the regulatory and catalytic domains of the ADAMs executes Notch proteolysis in normal and oncogenic
signaling. Structural features that distinguish the ADAM10 active site from that of ADAM17 can then be used to
guide development of highly selective ADAM10 or ADAM17 inhibitors.
ii) What is the molecular mechanism of engagement of the transcriptional machinery by Notch nuclear
complexes? Binding of intracellular Notch (ICN) to the RBPJ transcription factor in the nucleus leads to MAML
recruitment, but how Mastermind-like proteins (MAMLs) cooperate with Notch-RBPJ complexes to induce
transcription remains a fundamental unresolved question in the field. By defining the sequence of events
connecting Notch1 signaling and MAML1 recruitment to gene expression changes, we will illuminate the role of
MAML in the response of cancer cells to Notch activation.
iii) What is the molecular mechanism of feedback regulation by Notch transcriptional targets? As a core
transcriptional target regulated by Notch in diverse cell types, NRARP is an integral part of the Notch signal
transduction circuitry, acting as a negative feedback regulator of signaling by binding to the core Notch
transcription complex. Our goals will be to elucidate the structural basis for NRARP recruitment to the Notch
transcription complex, uncover the molecular mechanism underlying assembly of NRARP inhibitory complexes,
and elucidate the molecular mechanism underlying NRARP inhibition. Together, these studies will uncover a
central mechanism of Notch signal modulation, and create opportunities for development of novel regulators of
Notch signaling.

## Key facts

- **NIH application ID:** 10447804
- **Project number:** 5R35CA220340-06
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Stephen C. Blacklow
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $996,608
- **Award type:** 5
- **Project period:** 2017-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10447804

## Citation

> US National Institutes of Health, RePORTER application 10447804, Notch Signaling in Cancer (5R35CA220340-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10447804. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*