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

Award Number: R03TR003660
ORGANIZATION: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = -$1,996 )
2023	2021	THE PENNSYLVANIA STATE UNIVERSITY	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Trans-NIH Research Support	000	1	4/4/2023	NEW	-$1,996
														Subtotal = -$1,996

Issue Date FY: 2021 ( Subtotal = $160,500 )
2021	2021	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Trans-NIH Research Support	000	1	4/22/2021	NEW	$160,500
														Subtotal = $160,500

Grand Total All Awards = $158,504

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

Award Number: R03TR003660

ORGANIZATION: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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