# Deciphering the mechanism of SHIP1 regulation in human neutrophils

> **NIH NIH R01** · UNIVERSITY OF OREGON · 2022 · $78,598

## Abstract

Abstract
Immune cells interpret chemical cues in their environment and make decisions that control their
fate. For example, human neutrophils often respond to signals by polarizing and migrating
toward the chemical source. Critical for these cellular functions is the dynamic interplay between
cell surface receptors, small GTPases, and the enzymes that synthesize phosphatidylinositol
phosphate (PIP) lipids. This study aims to decipher the mechanisms the control communication
between these different classes of signaling molecules at the plasma membrane. Using human
neutrophils, we find that Cdc42 GTPase and a lipid phosphatase denoted SHIP1 trigger a
molecular signal that propagates across the plasma membrane in the form of a traveling wave.
This behavior, coined excitability, involves repetitive cycles of protein recruitment ON and OFF
the membrane. The goal of this study is to determine how SHIP1 regulates the excitable
signaling network by integrating signals derived from lipids and membrane tethered proteins.
Using a variety of in vitro biochemistry techniques, including supported membrane technology
and single molecule imaging, we will determine how lipid composition controls SHIP1
membrane association and phosphatase activity (Aim 1). Using factors that regulate the
excitable signaling network in cells, we will reconstitute mechanisms that control SHIP1
membrane recruitment, release of autoinhibition, and activation (Aim 2). In parallel, we will use
CRISPR based genome editing, optogenetics, and quantitative live cell imaging of fluorescent
biosensors to elucidate how communication between PIP lipids and small GTPase is regulated
by SHIP1. Using these tools we will determine the role SHIP1 serves as signaling network
scaffold versus a lipid phosphatase (Aim 3). Overall, this study will unify membrane biophysics
and cell biology to explain how PIP lipids, small GTPases, and SHIP1 synergistically control the
excitable signaling network and cell migration in neutrophils. By unraveling how white blood
cells sense, interpret, and respond to pathogenic signals we will fill a gap in knowledge
concerning how these signaling molecules coordinate cellular movement with the underlying
excitable network. This discovery could open doors for researchers to develop new therapeutics
that can be used to modulate immune cell functions in ways that combat infection, inflammation,
and cancer.

## Key facts

- **NIH application ID:** 10582013
- **Project number:** 3R01GM143406-02S1
- **Recipient organization:** UNIVERSITY OF OREGON
- **Principal Investigator:** Scott David Hansen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $78,598
- **Award type:** 3
- **Project period:** 2021-07-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10582013

## Citation

> US National Institutes of Health, RePORTER application 10582013, Deciphering the mechanism of SHIP1 regulation in human neutrophils (3R01GM143406-02S1). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10582013. Licensed CC0.

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