# Identifying endosomal Phosphatidylinositol 4-phosphate 5-kinase isoforms regulating growth factor stimulated integrin recycling and migration

> **NIH NIH R03** · PENNSYLVANIA STATE UNIVERSITY, THE · 2021 · $160,500

## Abstract

PROJECT SUMMARY
Epithelial cells are normally non-motile but can become migratory in response to growth factor signaling.
Growth factor stimulated migration plays important roles in development and is an early step in the repair
process after tissue damage. During cancer progression however, growth factor signaling can become
aberrantly activated through oncogenic mutation or the actions of stromal cells in the tumor microenvironment.
Growth factor stimulated migration of carcinoma cells promotes metastasis and further disease progression. A
thorough understanding of the signals that initiate migration in response to growth factor signaling is essential
for developing interventions to either enhance migration during wound healing or inhibit adhesion and
migration of cancer cells. Focal adhesions attach cells to the extracellular matrix and allow the generation of
traction forces that cells use to migrate. By necessity, growth factor stimulated migration requires increased
assembly of new focal adhesions, which are organized by integrins. Growth factor stimulation leads to the
rapid recycling of previously internalized integrins to the plasma membrane. Previous work in the Santy lab
demonstrated that cytohesin activity is required for stimulated integrin recycling and that only those cytohesin
splice variants that bind phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) can initiate this trafficking process.
PI(4,5)P2 is produced locally where needed from PI4P by phosphatidylinositol 4-phosphate 5-kinases
(PIP5Ks), implicating PIP5Ks in the stimulated recycling of integrins. Previous work on these understudied
kinases has predominately focused on their actions at the plasma membrane during signaling and
internalization of membrane proteins. The proposed studies will determine which PIP5K isoforms are required
for stimulated integrin recycling and determine where within the endosomal system they produce PI(4,5)P2 to
initiate stimulated integrin recycling. A knockdown and rescue strategy will be used to test the impact of PIP5K
splice isoforms on integrin recycling. The location where these isoforms act will be determined by localization
of both the isoforms and their product, PI(4,5)P2. In an orthogonal approach, chemically induced dimerization
will be used to recruit PI(4,5)P2 producing and consuming enzymes to individual endosomal compartments to
determine where local production of this lipid is required to stimulate the return of integrins to the cell surface.
Understanding the steps that lead to growth factor stimulated integrin recycling will allow development of
interventions to modulate this process without affecting growth factor signaling as a whole.

## Key facts

- **NIH application ID:** 10217317
- **Project number:** 1R03TR003660-01
- **Recipient organization:** PENNSYLVANIA STATE UNIVERSITY, THE
- **Principal Investigator:** Lorraine C Santy
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $160,500
- **Award type:** 1
- **Project period:** 2021-05-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10217317

## Citation

> US National Institutes of Health, RePORTER application 10217317, Identifying endosomal Phosphatidylinositol 4-phosphate 5-kinase isoforms regulating growth factor stimulated integrin recycling and migration (1R03TR003660-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10217317. Licensed CC0.

---

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