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Regulation of endothelial podosome formation by tyrosine phosphatase Shp2 and endothelial nitric oxide synthase

Award Number: F31HL186759
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/11/2026
PERIOD OF PERFORMANCE END DATE: 12/10/2027

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Regulation of endothelial podosome formation by tyrosine phosphatase Shp2 and endothelial nitric oxide synthase - ABSTRACT Angiogenesis is a tightly regulated multistep process crucial for providing nutrients and oxygen to all tissues. The first step of angiogenesis is matrix degradation, in which endothelial cells dissolve the surrounding matrix, creating space for tip cell migration. To start the degradation process, endothelial cells form multiprotein actin-based structures called podosomes. Podosomes are highly dynamic matrix adhesion structures, and their formation is initiated through tyrosine phosphorylation of multiple podosomal proteins by tyrosine kinase Src. Interestingly, we have found that the tyrosine phosphatase Shp2 is also necessary and sufficient to induce the formation of podosomes. However, this role does not require the catalytic activity of Shp2 and occurs primarily through its scaffolding function, suggesting a novel mechanism for regulating podosomes through inactive Shp2. Here, we propose to define the role of Shp2 in regulating podosomes and determine the potential mechanisms that regulate the catalytic function of Shp2 to make it a scaffolding protein. One of the known pathways to control Shp2 activity is nitrosylation of its critical catalytic cysteine. Endothelial nitric oxide synthase (eNOS) plays an important role in angiogenesis, yet its role in the regulation of endothelial podosomes is unknown. We hypothesize that by generating NO locally, eNOS inactivates Shp2 and makes it a protein scaffold. We found that eNOS localizes to active podosomes and eNOS activity is required for podosome formation downstream of Src and Shp2. Importantly, a catalytically inactive mutant of Shp2 can still induce the formation of podosomes even when eNOS is inhibited, suggesting that the primary role of eNOS in regulating podosomes is the inactivation of Shp2. Our proposed studies will focus on identifying Shp2 interactions that mediate podosome regulation and further dissection of the mechanism by which eNOS controls Shp2 function. Our research into the novel roles of eNOS and Shp2 will provide crucial insights into the regulation of the initial step of angiogenesis.


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: 2026 ( Subtotal = $50,114 )
2026	2026	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Cardiovascular Diseases Research	000	1	6/16/2026	NEW	$50,114
														Subtotal = $50,114

Grand Total All Awards = $50,114

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Regulation of endothelial podosome formation by tyrosine phosphatase Shp2 and endothelial nitric oxide synthase

Award Number: F31HL186759

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/11/2026

PERIOD OF PERFORMANCE END DATE: 12/10/2027

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