# SHP1 Phosphatase/SYK Kinase Balance Controls the Actin Economy and Macropinocytosis in Macrophages

> **NIH NIH P20** · SOUTH DAKOTA STATE UNIVERSITY · 2022 · $351,336

## Abstract

Project Summary/Abstract
Macropinocytosis, or “cell drinking,” is central to several macrophage functions including wound healing,
antigen presentation, and resolution of inflammation. However, there are large gaps in the mechanistic
understanding of this process. The long-term goal of this project is to identify novel mediators and cellular
mechanisms of macropinocytosis. The overall objective is to investigate how macrophages regulate actin
dynamics, phosphoinositide signaling and macropinocytotic efficiency in response to pro- and anti-
inflammatory stimuli. The central hypothesis is that the balance of SHP1 phosphatase and SYK kinase activity
optimizes the macrophage “actin economy” for macropinocytosis or other actin-dependent processes
depending on the activation state of the cell. This hypothesis stems from preliminary CRISPR/Cas9 whole
genome screen data produced in the applicant's laboratory indicating that SHP1 and SYK are key regulators of
macropinocytosis. The hypothesis will be tested by pursuing two specific aims: 1) Determine the effect of
SYK/SHP1 balance on actin dynamics and phosphoinositide signaling at forming macropinosomes; and 2)
Determine how ITAM and ITIM containing immune receptors modulate macropinocytosis via the SHP1/SYK
balance in resting and activated macrophages. Under the first aim, an already proven live-cell imaging
approach established by the applicant will be used to image actin and phosphoinositide dynamics in wildtype
or CRISPR/Cas9 gene-disrupted primary murine macrophages with resting, inflammatory, or anti-inflammatory
activation states. Under the second aim, mechanisms of SHP1 and SYK activation by recruitment to immune
receptors will be tested using fluorescent protein chimeras of SHP1 or SYK in wild type or gene-disrupted
macrophages in response to inflammatory or anti-inflammatory stimuli. This approach is innovative because
the hypothesis was generated from novel mediators of macropinocytosis identified by a CRISPR/Cas9 whole
genome screen. Furthermore, this strategy uses targeted gene disruptions in combination with cellular
fluorescent probes and advanced live-cell microscopy techniques for three-dimensional live-cell imaging of the
spatiotemporal dynamics of actin polymerization and phosphoinositide signaling during macropinocytosis. The
proposed research is significant because it is expected to expand the understanding of novel mechanisms
macropinocytosis and the role of macropinocytosis in inflammation. Ultimately, such knowledge has the
potential to identify therapeutic targets for modulation of macropinocytosis efficiency and the treatment of
inflammatory diseases such as chronic wounds or auto-immune disorders.

## Key facts

- **NIH application ID:** 10335541
- **Project number:** 1P20GM135008-01A1
- **Recipient organization:** SOUTH DAKOTA STATE UNIVERSITY
- **Principal Investigator:** Natalie Wendt Thiex
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $351,336
- **Award type:** 1
- **Project period:** 2022-03-20 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10335541

## Citation

> US National Institutes of Health, RePORTER application 10335541, SHP1 Phosphatase/SYK Kinase Balance Controls the Actin Economy and Macropinocytosis in Macrophages (1P20GM135008-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10335541. Licensed CC0.

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