Regulation of endothelial podosome formation by tyrosine phosphatase SHP2 and endothelial nitric oxide synthase

Active Project Grant Awarded Last action

Award ID
F31HL186759
Recipient
Awarding agency
Obligated
$50,114

Award facts

Assistance listing
93.837 Cardiovascular Diseases Research
Completion date 0% complete
Place of performance
Chicago, IL 60612, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

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.

Quick answers

Who received award F31HL186759?

F31HL186759 was awarded to University Of Illinois by National Heart Lung and Blood Institute (National Institutes of Health) on December 11, 2026.

How much is award F31HL186759 worth?

$50,114 has been obligated on F31HL186759.

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